JPH0725759B2 - Substituted pyridopyrimidinones and related heterocycles as angiotensin II antagonists - Google Patents

Description

Detailed Description of the Invention

The present invention relates to novel substituted pyridopyrimidinones and related heterocyclic compounds useful as angiotensin II antagonists in the treatment of elevated blood pressure and congestive heart failure. Therefore, the substituted pyridopyrimidinone compounds of the present invention are useful as antihypertensive agents.

The renin-angiotensin system (RAS) plays a central role in the regulation of normotension and is believed to be critically involved in the development and maintenance of hypertension and congestive heart failure. The octapeptide hormone angiotensin II (AII) is angiotensin-converting enzyme (ACE) localized in the endothelium of blood vessels in the lung, kidney and many other organs.
It is produced mainly in the blood during the degradation of angiotensin I by Escherichia coli and is the final product of RAS. AII is a powerful arterial vasoconstrictor that exerts its action by interacting with specific receptors present on the cell membrane. One of the possible ways to regulate RAS is angiotensin II receptor antagonism. Several peptide analogs of AII are known to competitively block the receptor and suppress the action of this hormone, but their experimental and clinical application is limited by partial agonist activity and lack of oral absorption. [M.
Antonaccio Clin Exp. Hypertens. A
4.27-46 (1982), D.I. H. P. Streeten and G.W. H. Anderso
n), Jr. Handbooks of Hypertension, Clinical Pharmacology of Anti-Hypertensive Drugs, A. E. Doyle
Ed., Volume 5, pp. 246-271, Elsevier Science Publisher, Amsterdam, Netherlands, 1984.
Year].

Recently several non-peptide compounds have been described as AII antagonists. Specific examples of this compound include U.S. Pat. Nos. 4,207,324 and 4,340,598,
Nos. 4,576,958, 4,582,847 and 4,880,804, European Patent Application No. 02.
No. 8.834, No. 245.637, No. 253.3.
No. 10, No. 291.969, No. 323.841 and No. 324.377, and A.I. T. Chiu and others [Eur.JP
harm.Exp.Therap. Vol. 157, pp. 13-21 (198)
8 years)] and P. C. Wong, etc., [J.Pham.Exp.
Therap. Vol. 247, pages 1-7 (1988), Hypertension, vol. 13, pages 489-497 (19).
1989)]. All of the U.S. patents, European Patent Applications 0288834 and 253.310, and two articles generally disclose substituted imidazole compounds linked to a substituted phenyl by a lower alkyl bridge. European Patent Application No. 245.63
No. 7 discloses 4,5,6,7-tetrahydro-2H-imidazo [4,5-C] -pyridine-6-carboxylic acid derivatives and their analogs as hypotensive agents.

The present invention is an angiotensin II-like hypotensive agent for the treatment of congestive heart failure and the treatment of elevated intraocular pressure.
The present invention relates to novel substituted pyridopyrimidinones and related heterocyclic compounds useful as antagonists. The compounds of the present invention have the general formula (I):

[Chemical 14] [In the Formula, M is a C atom. L is C or N and when attached to K or J forms a ring as defined below. J is -C (= Y)-(Y is O or NR ²¹ ) and K
And L are joined together to form a 6-membered aromatic ring containing one N atom and five C atoms which is not K, and the carbon atom is replaced by R ⁷ , R ^8a and R ^8b You can K is -C
(= Y)-(Y is O or NR ²¹ ), and J and L
Are bound together by 1 N atom and not 5 C by J
Form a 6-membered aromatic ring containing atoms, and the carbon atom is R
⁷ , R ^8a and R ^8b can be substituted. However, only one of J and K is -C (= Y)-.

R ¹ is (a) -CO ₂ R ⁴ , (b) -SO
^{_{3 R 5, (c) -NHSO}} 2 CF 3, (d) -PO (O
_{^{R 5) 2, (e)}} -SO 2 -NH-R 9, (f) -CO
NHOR ⁵ , (g) -C (OH) (R ⁹ ) -P (= O)
^{(OR 5) (OR 5)} , (h) -P (= O) (OR 5)
_{^{-R 9, (i) -SO 2}} NH- heteroaryl as defined below, -CH ₂ SO ₂ as defined below (j) NH-
_{Heteroaryl, (k) -SO 2 NH-} CO-R 22,
_{(L) -CH 2 SO 2 NH} -CO-R 22, (m) -CO
^{_{NH-SO 2 R 22, (}} n) -CH 2 CONH-SO 2 R
_{^{22, (o) -NHSO 2 NHCO}} -R 22, (p) -NH
CONHSO ₂ -R ²² ,

[Chemical 15]

[Chemical 16] _{(T) -CONHNHSO 2 CF 3,} (u) -SO 2 N
H-CN,

[Chemical 17] ^{(X) -PO (OR 5)} (OR 4), (y) -SO 2 N
HCONR ⁴ R ²² , {heteroaryl may optionally contain 1 to 3 heteroatoms selected from the group consisting of O, N or S, unsubstituted, monosubstituted or disubstituted 5 or It is a 6-membered aromatic ring, and the substituent is -O.
_{H, -SH, -C 1 ~C 4} - alkyl, -C ₁ ~C ₄ -
Alkoxy, -CF _3, halo (Cl, Br, F, I ),
_{-NO 2, -CO 2 H, -CO} 2 - (C 1 ~C 4 - _{alkyl), - NH 2, -NH (} C 1 ~C 4 - alkyl) and -N (C ₁ ~C ₄ - alkyl) It is a group selected from the group consisting of ₂ }.

R ^2a and R ^2b are each independently (a) H, (b) halogen, (Cl, Br, I, F),
(C) NO ₂ , (d) NH ₂ , (e) C ₁ -C ₄ -alkylamino, (f) di (C ₁ -C ₄ -alkyl) amino, (g) SO ₂ NHR ⁹ , (h). CF ₃ , (i) C ₁
-C ₆ - _{alkyl, (j) C 1 ~C 6} - alkoxy,
(K) C ₁ ~C ₆ - alkyl _{-S -, (l) C 2} ~C 6
- _{alkenyl, (m) C 2 ~C 6} - alkynyl, (n)
Aryl as defined below, (o) aryl (C ₁ -C
₄ - _{alkyl), (p) C 3 ~C} 7 - cycloalkyl.

R ^3a is (a) H, (b) halo (Cl, B
r, I, F), (c) C ₁ -C ₆ -alkyl, (d) C
₁ -C ₆ - _{alkoxy, (e) C 1 ~C 6} - alkoxyalkyl. R ^3b is (a) H, (b) halo (Cl, Br, I, F),
(C) NO ₂ , (d) C ₁ -C ₆ -alkyl, (e) C
₁ -C ₆ - _{acyloxy, (f) C 3 ~C 7} - _{cycloalkyl, (g) C 1 ~C 6} - alkoxy, (h) -NH
SO ₂ R ⁴ , (i) hydroxy (C ₁ -C ₄ -alkyl), (j) aryl (C ₁ -C ₄ -alkyl),
(K) C ₁ ~C ₄ - _{alkylthio, (l) C 1 ~C 4} -
_{Alkylsulfinyl, (m) C 1 ~C 4} - _{alkylsulfonyl, (n) NH 2, (} o) C 1 ~C 4 - alkylamino, (p) di (C ₁ ~C ₄ - alkyl) amino,
(Q) fluoro -C ₁ -C ₄ - alkyl -, (r) -S
O ₂ —NHR ⁹ , (s) aryl defined below,
(T) _{furyl, (u) CF 3, (} v) C 2 ~C 6 - _{alkenyl, (w) C 2 ~C 6} - alkynyl, {aryl halogen (Cl, Br, I, F ), N (R
⁴ ) ₂ , CO ₂ R ⁴ , C ₁ -C ₄ -alkyl, C ₁ -C
₄ - _{alkoxy, NO 2, CF 3, C} 1 ~C 4 - is alkylthio or one or two phenyl or naphthyl which is optionally substituted with substituents selected from the group consisting of OH}.

R^Four Is H, aryl as defined above or
Optionally substituted with a defined aryl or heteroaryl
Straight or branched chain C₁ ~ C₆ -Alkyl. R^4aIs
Any of the above defined aryls or the above defined aryls
A straight chain or branched chain C substituted with₁ ~ C₆ -Alkyl
It R^Five Is H, -C (R^Four ) H-O-C (= O) -R^4a
Is. E is a single bond, -NR¹³(CH₂ ) S-, -S
(O) x (CH₂ ) S- (x is 0 to 2, S is 0 to
5), -CH (OH)-, -O-, CO-.
It R⁶ Is (a) halo (Cl, Br, I, F), -O-
C₁ ~ C_Four -Alkyl, C₁ ~ C_Four -Alkyl, -NO
₂ , -CF₃ , -SO₂ NR⁹ R^Ten, -SC₁ ~ C_Four 
-Alkyl, -OH, -NH₂ , C₃ ~ C₇ -Cycloa
Rukiru, C₃ ~ C_Ten -Selected from the group consisting of alkenyl
Optionally substituted with one or two substituents
Aryl, (b) straight chain or branched chain C₁ ~ C₆ -Archi
Le, C₂ ~ C_Five -Alkenyl or C₂ ~ C_Five -Arkini
Lu {aryl, C as defined above, respectively₃ ~ C₇ -Cycloa
Rukiru, halo (Cl, Br, I, F), CF₃ , CF₂ 
CF₃ , -NH₂ , -NH (C₁ ~ C_Four -Alkyl),
-OR^Four , -N (C₁ ~ C_Four -Alkyl)₂ , -NH-
SO₂ R^Four , -COOR^Four , -SO₂ NHR⁹ Consists of
Can be optionally substituted with a substituent selected from the group
Or (c) 1 selected from the group consisting of N, O and S
Unsubstituted, monosubstituted which may contain up to 3
Or di-substituted heteroaromatic 5- or 6-membered ring {substituted
The groups are -OH, -SH, C₁ ~ C_Four -Alkyl, C₁ ~ C
_Four -Alkoxy, -CF₃ , Halo (Cl, Br, I,
F) or NO₂ A group selected from the group consisting of} (d) C₃ ~ C₇ -Cycloalkyl, (e) perfluor
RO-C₁ ~ C_Four -Alkyl, (f) H.

R ⁷ is (a) H, (b) straight chain or branched chain C
₁ -C ₆ - alkyl, C ₂ -C ₆ - alkenyl or C ₂
-C ₆ - alkynyl, (c) halo (Cl, Br, I,
F) or (d) CF ₃ .

[0010] R ^8a and R ^8b are independently (a) H, (b) -OH, - guanidino, C ₁ ~C ₄ -
_{^{Alkoxy, -N (R 4) 2,}} COOR 4, -CON
_{^{(R 4) 2, -O-}} COR 4, - aryl, - heteroaryl, -S (O) x-R 22, - _{^{tetrazol-5-yl, -CONHSO 2 R 22, -SO 2}} NH- heteroaryl, ^{_{-SO 2 NHCOR 22, -PO (OR}} 4) 2, -
^{PO (OR 4) R 9,} -SO 2 NH-CN, -NR 10 C
OOR ²² , C ₁ -C ₈ -alkyl optionally substituted with a substituent selected from the group consisting of — (CH ₂ ) _1-4 R ⁴ .
(C) -CO- _{aryl, (d) -C 3 ~C 7} - cycloalkyl, (e) halo (Cl, Br, I, F ), (f)
^{-OH, (g) -OR 22,} (h) -C 1 ~C 4 - perfluoroalkyl, (i) -S (O) x-R 22, (j) -
COOR ⁴ , (k) -SO ₃ H, (l) -NR ⁴ R ²² ,
(M) -NR ⁴ COR ²² , (n) -NR ⁴ COOR ²² ,
^{_{(O) -SO 2 NR 4 R}} 9, (p) -NO 2, (q) -
_{^{N (R 4) SO 2 R}} 22, (r) -NR 4 CONR 4
^{R 22, (s) -OC (} = O) NR 22 R 9, as defined above (t) - aryl or - heteroaryl, (u) -NH
_{SO 2 CF 3, (v)} -SO 2 NH- heteroaryl,
^{_{(W) -SO 2 NHCOR 22,}} (x) -CONHSO 2
^{R 22, (y) -PO (} OR 4) 2, (z) -PO (OR
⁴ ) R ⁴ , (aa) -tetrazol-5-yl, (b
b) -CONH (tetrazol-5-yl), (cc)
_{^{-COR 4, (dd) -SO 2}} NHCN, (ee) -N
_{^{R 4 SO 2 NR 4 R 22}} , (ff) -NR 4 SO 2 O
^{R 22, (gg) -CONR 4} R 22,

[Chemical 18] Is.

R ⁹ is H, C ₁ -C ₅ -alkyl, aryl or arylmethyl. R ¹⁰ is H, C _{1 to} C ₄ −
It is alkyl. R ¹¹ is H, C ₁ -C ₆ -alkyl, C
₁ -C ₄ - alkenyl, C _{1 ~C 4} - alkoxyalkyl or

[Chemical 19] Is. R ¹² is -CN, a -NO ₂ or -CO ₂ R ^4. R ¹³ is H, (C ₁ -C ₄ -alkyl) CO—, C ₁
-C ₆ - alkyl, allyl, C ₃ -C ₆ - cycloalkyl, aryl or arylmethyl. R ¹⁴ is H, C
₁ -C ₈ - alkyl, C ₁ -C ₈ - cycloalkyl, aryl or arylmethyl - perfluoroalkyl, C ₃ -C _6. R ¹⁵ is H, C ₁ -C ₆ -alkyl. R ¹⁶ is H, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, aryl or arylmethyl. R
^{17 -NR 9 R 10, -OR 10,} -NHCONH 2, -N
HCSNH ₂ ,

[Chemical 20] Is. R ¹⁸ and R ¹⁹ are independently C ₁ -C ₄ -alkyl or are linked together to — (CH ₂ ) q— (q is 2
Or 3).

R ²⁰ is H, --NO ₂ , --NH ₂ , --OH or --OCH ₃ . R ²¹ is aryl as defined above in (a), heteroaryl as defined above in (b), aryl as defined above in (c), heteroaryl as defined above, —OH, —NH ₂ , —NH.
(C ₁ ~C ₄ - _{alkyl), - N (C 1 ~C} 4 - alkyl) _2, -CO ₂ R ^4a, halo (Cl, Br, F, I ),
C ₁ optionally substituted with substituents selected from the group consisting of -CF ₃ -C ₄ - alkyl. R ²² is aryl as defined above in (a), heteroaryl as defined above in (b), (c) C ₃ -C ₇ -cycloalkyl, aryl as defined above in (d), heteroaryl as defined above, _{-OH, -SH, C 1 ~C 4} - alkyl, -
O (C ₁ ~C ₄ - _{alkyl), - S (C 1 ~C} 4 - alkyl), - CF _3, halo (Cl, Br, F, I ), - N
_{O 2, -CO 2 H, CO} 2 - (C 1 ~C 4 - _{alkyl), - NH 2, -NH (} C 1 ~C 4 - alkyl), -
N (C ₁ ~C ₄ - _{alkyl) 2, -PO 3 H 2,} -PO
_{(OH) (O-C 1} ~C 4 - alkyl), - PO (OR
⁴⁾ C is optionally substituted with substituents selected from the group consisting of R ⁹ ₁ ~C ₆ - alkyl, (e) perfluoro -C
₁ -C ₄ - alkyl.

X is (a) carbon-carbon single bond, (b) -C
O-, (c) -O-, (d) -S-, (e) -N
^{(R 13) -, (f} ) -CON (R 15) -, (g) -N
^{(R 15) CO -, (} h) -OCH 2 -, (i) -CH 2
_{O -, (j) -SCH 2} -, (k) -CH 2 S-,
^{(L) -NHC (R 9)} (R 10), (m) -NR 9 SO
_{2 -, (n) -SO 2} NR 9 -, (o) -C (R 9)
^{(R 10) NH -, (} p) -CH = CH -, (q) -CF
= CF-, (r) -CH = CF-, (s) -CF = CH
_{-, (t) -CH 2 CH} 2 -, (u) -CF 2 CF 2
-,

[Chemical 21] ^{(W) -C (OR 14)} H -, (x) -C (OCOR 16)
H-, (y) -C (= NR ¹⁷ )-, or

[Chemical formula 22] Is. r is 1 or 2. } And its pharmaceutically usable salts.

One embodiment of the compound of formula (I) is one N atom wherein M is a C atom, J is -C (O)-, and K and L are joined together and are not K. And forming a 6-membered aromatic ring containing 5 C atoms, the carbon atom can be substituted by R ⁷ , R ^8a and R ^8b , wherein R ¹ is (a) -COO.
H,

[Chemical formula 23] _{(C) -NH-SO 2 CF} 3, -S defined above (d)
O ₂ NH- heteroaryl, -CH defined above (e)
₂ SO ₂ NH-heteroaryl, (f) -SO ₂ NH-
^{CO-R 22, (g)} -CH 2 SO 2 NH-CO-R 22,
_{(H) -CONH-SO 2 R} 22, (i) -CH 2 CON
^{_{H-SO 2 R 22, (}} j) -NHSO 2 NHCO-R 22,
(K) -NHCONHSO is a ₂ -R ^22,

R ^2a is H and R ^2b is H, F, Cl, C
F ₃ , C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl or aryl, R ^3a
Is H and R ^3b is H, F, Cl, CF ₃ , C ₁ -C ₄
- alkyl, C ₂ -C ₄ - alkenyl, C ₂ -C ₄ - alkynyl, C ₅ -C ₆ - cycloalkyl, -COOCH
_{3, -COOC 2 H 5, -SO} 2 -CH 3, NH 2, -
N (C ₁ ~C ₄ - alkyl) ₂ or -NH-SO ₂ CH
₃ , E is a single bond, —O— or —S—, and R ⁶
There (a) C ₃ ~C ₅ - cycloalkyl, Cl, CF _{3,
CCl 3, -O-CH 3,} -OC 2 H 5, -S-CH
_{3, -S-C 2 H 5} , C 1 ~C 5 which is optionally substituted with substituents selected from the group consisting of phenyl or F - _{alkyl, (b) C 2 ~C 5} - alkenyl or C ₂ ~ C ₅ - alkynyl _{or, (c) C 3 ~C 5} - cycloalkyl, R ⁷ is H,

R ^8a and R ^8b are independently (a) H (b) COOR ^4a , OCOR ^4a , OH, aryl or-
(CH ₂₎ C ₁ optionally substituted with _1-4 R ⁴ _{~C 8} - ^{alkyl, (c) OR 22, (} d) -OH, (e) -NO 2, (f) -N (R 4 ^{) -C (= O) -R 22} , (g) -CONR 4 R 22, (h) -NR 4 -C (= O) -O-R 22, (i) -NR 4 R 22, (j) halo (Cl, F, Br), (k) -CF 3, (l) -CO 2 R 4a, as defined above (m) -CO- aryl, (n) -S (O) x-R 22, ^{_{(o) -SO 2 -NR 4 R}} 9, (p) -N (R 4) SO 2 R 22, aryl as defined above (q), (r) -NR 4 CONR 4 R 22, (s) - N (R ⁴ ) SO ₂ N (R ⁴ ) R ²² , X is a single bond, and r is 1.

A class of this embodiment is that R ¹ of formula (I) is (a) -COOH

[Chemical formula 24] _{(C) -NH-SO 2 -CF} 3, as defined above (d) -
SO ₂ NH- _{heteroaryl, (e) -SO 2 NH-} C
O-R ^22, (f) a -CONH-SO ₂ R ^22, E is a single bond, r is ^{1, R 2a, R 2b,} R 3a and R
^3b are each H, -C ₁ ~C ₆ - alkyl, -C ₂ ~C ₆ -
Alkenyl, -C ₂ ~C ₆ - alkynyl, -Cl, -
F, -NO _2, a -CF _3, ^{R 6} is -C ₁ -C ₄
- alkyl, - cyclopropyl, -CH ₂ CH ₂ CH _{2
CF 3, -CH 2 CH 2 CF} 3, -C 2 ~C 5 - alkenyl, - cyclopropylmethyl, H are independently R ^8a and R ^8b are each, -C ₁ -C ₄ - alkyl, -NO ₂ ,
_{^{-NR 4 R 22, -OCH 3,}} -NR 4 COOR 22, -C
^{_{l, -CH 2 COOR 4a, -S}} (O) x-R 22 ^{alkyl, NR 4 CONR 4 R 22,} CH 2 OCO (C 1 ~C 4
- ^{alkyl), NR 4 COR 22, CO} 2 R 4a, -F, -
CH ₂ Ph, is a compound which is -CONR ⁴ R ^22.

As a subclass, R ¹ of formula (I) is (a) COOH,

[Chemical 25] ^{_{(C) -SO 2 NHCOR 22,}} (d) -CONHSO 2
R ^22, a _{(e) -NHSO 2 CF 2 CF} 3, R 2a
R ^2b, R ^3a and R ^3b are each H, -C ₁ -C ₄ - alkyl, -Cl or F, R ⁶ is-n-propyl, ethyl,-n-butyl, - trans-2-butenyl, CH _{2
CH 2 CF 3, -CH 2 CH} 2 CH 2 CF 3, - cyclopropyl, - cyclopropyl methyl, R ^8a and R
^8b each independently is _{H, -NO 2, -C 1 ~C} 4 - _{alkyl, -NH 2, -NHCOCH 3, -NHCH} 3, -S
^{(O) x-R 22,} -N (CH 3) 2, -OCH 3, -C
_{OOH, -COOCH 3, -CH 2 OCOCH} 3, C
_{l, -CH 2 COOCH 3, -N} (R 4) CON (R
⁴ ) ₂ , -N (R ⁴ ) CO ₂ R ⁴ , -CH ₂ COOH,
^{-N (R 4) COR 22,} -OCH 3, CH 2 OH, NH
It is a compound that is Me, CH ₂ Ph.

Specific examples of this subclass are the following compounds: (1) 2-n-butyl-1-[(2′-carboxybiphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (1H) -one, (2) 2-n- Butyl-1-
[(2 '-(Tetrazol-5-yl) biphen-4-
Il) methyl] pyrido [2,3-d] pyrimidine-4
(1H) -one, (3) 2-n-butyl-1-[(2 '
-(Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [3,2-d] pyrimidin-4 (1H)-
On, (4) 2-n-butyl-1-[(2 ′-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [3,4-d] pyrimidin-4 (1H) -one,
(5) 2-n-butyl-1-[(2 ′-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [4,3-d] pyrimidin-4 (1H) -one, (6 )
2-n-butyl-6-methyl-1-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (1H) -one,
(7) 6-amino-2-n-butyl-1-[(2'-
(Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (1H) -one, (8) 2-n-butyl-1-[(2 '-(tetrazole -5-yl) biphen-4-yl) methyl-8-methyl] pyrido [4,3-d] pyrimidin-4 (1H)-
ON, (9) 2-n-butyl-1-5-methyl-
[(2 '-(Tetrazol-5-yl) biphen-4-
Il) methyl] pyrido [3,4-d] pyrimidine-4
(1H) -one, (10) 2-n-butyl-5,7-dimethyl-1-[(2 ′-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d ] Pyrimidin-4 (1H) -one, (11) 6-amino-2-
n-Butyl-5-methyl-1-[(2 ′-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (1H) -one, (1
2) 2-n-butyl-5-methyl-7-methylamino-
1-[(2 '-(tetrazol-5-yl) biphen-
4-yl) methyl] pyrido [2,3-d] pyrimidine-
4 (1H) -one, (13) 1-[(2 ′-(N-benzoylsulfonamido) biphen-4-yl) methyl]
-2-n-butyl-5,7-dimethylpyrido [2,3-
d] pyrimidin-4 (1H) -one and (14) 2-n
-Butyl-5,7-dimethyl-1-[(2 '-(N-trifluoromethylsulfonylcarboxamido) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (1H) -one,

In a second embodiment, M in formula (I) is a C atom, K is --C (O)-, and J and L are joined together to form one N atom which is not J. And a compound capable of forming a 6-membered aromatic ring containing 5 C atoms and substituting R ⁷ , R ^8a and R ^8b for the carbon atom. The classes and subclasses of this embodiment are the same as described above.

Specific examples of this subclass are the following compounds: (1) 2-n-butyl-3-[(2′-carboxybiphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H) -one, (2) 2-n- Butyl-3-
[(2 '-(Tetrazol-5-yl) biphen-4-
Il) methyl] pyrido [2,3-d] pyrimidine-4
(3H) -one, (3) 2-n-butyl-3- [2'-
(Carboxybiphen-4-yl) methyl] pyrido [3,2-d] pyrimidin-4 (3H) -one, (4)
2-n-butyl-3-[(2 '-(tetrazole-5-
Il) biphen-4-yl) methyl] pyrido [4,3-
d] pyrimidin-4 (3H) -one, (5) 2-n-butyl-7-isopropyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [4. 3-d] pyrimidin-4 (3H) -one, (6)
6-amino-2-n-butyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H) -one,
(7) 6-acetamido-2-n-butyl-3-[(2 '
-(Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H)-
ON, (8) 2-n-butyl-5-methyl-3-
[(2 '-(Tetrazol-5-yl) biphen-4-
Il) methyl] pyrido [3,4-d] pyrimidine-4
(3H) -one, (9) 2-n-butyl-3-[(2 '
-(Tetrazol-5-yl) biphen-4-yl) methyl] -6-thiomethylpyrido [2,3-d] pyrimidin-4 (3H) -one, (10) 2-n-butyl-7-
Carboxy-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-
d] pyrimidin-4 (3H) -one, (11) 2-n-
Butyl-7- (N-isopropylcarbamoyl) amino-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [3,2-d] pyrimidin-4 (3H) -one , (12) 2-n-butyl-6-
(N-isobutyloxycarbonyl) amino-3-
[(2 '-(Tetrazol-5-yl) biphen-4-
Il) methyl] pyrido [2,3-d] pyrimidine-4
(3H) -one, (13) 2-n-butyl-6- [N-
(Morpholin-4-yl) carbamoyl) -N-methyl] amino-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-
d] pyrimidin-4 (3H) -one, (14) 2-n-
Butyl-6- (N-isopropyloxycarbonyl-N
-Methyl) amino-3-[(2 '-(tetrazole-5
-Yl) biphen-4-yl) methyl] pyrido [2,3
-D] pyrimidin-4 (3H) -one, (15) 6-
(N-benzyloxycarbonyl-N-methyl) amino-2-n-butyl-3-[(2 '-(tetrazole-5
-Yl) biphen-4-yl) methyl] pyrido [2,3
-D] pyrimidin-4 (3H) -one, (16) 3-
[(2 ′-(N-Benzoylsulfonamido) biphen-4-yl)] methyl-2-n-butyl-6- (N-isopropyloxycarbonyl-N-benzyl) aminopyrido [2,3-d] pyrimidine- 4 (3H) -on,
(17) 2-n-butyl-6- (N-isopropyloxycarbonyl-N-methyl) amino-3-[(2'-
(N-trifluoromethylsulfonylcarboxamide)
Biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H) -one, (18) 2-n-butyl-3-[(2 '-(tetrazol-5-yl) biphen- 4-yl) methyl] pyrido [3,2-d] pyrimidin-4 (3H) -one, (19) 6- [N-benzyl-N
-N-Butyloxycarbonyl] amino-2-propyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H)- ON, (20) 2-n-butyl-6-
(N-Methyl-N-isobutyloxycarbonyl) amino-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [3,2-d] pyrimidin-4 (3H)- On, (21) 6- (N-benzyl-
N-butanoyl) amino-2-n-propyl-3-
[(2 '-(Tetrazol-5-yl) biphen-4-
Iyl) methyl] pyrido [3,2-d] pyrimidine-4
(3H) -one, (22) 6- (N-benzoyl-N-
n-pentyl) amino-2-n-propyl-3-
[(2 '-(Tetrazol-5-yl) biphen-4-
Iyl) methyl] pyrido [3,2-d] pyrimidine-4
(3H) -one, (23) 6- (N- (p-chloro) benzoyl-Nn-pentyl) amino-2-n-propyl-3-[(2 '-(tetrazol-5-yl) biphene -4-yl) methyl] pyrido [3,2-d] pyrimidin-4 (3H) -one, (24) 6- (N- (p-chloro) benzoyl-N-isobutyl) amino-2-n-propyl -3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [3,2-d] pyrimidin-4 (3H) -one, (25) 6- (Nn- Propyl-N-isobutyloxycarbonyl) amino-2
-N-propyl-3-[(2 '-(tetrazole-5-
Il) biphen-4-yl) methyl] pyrido [3,2-
d] pyrimidin-4 (3H) -one, (26) 6- (N
-Benzoyl-Nn-pentyl) amino-3-
[(2 '-(N-benzoylsulfonamido) biphen-4-yl) methyl] -2-n-propylpyrido [3,3
2-d] pyrimidin-4 (3H) -one, (27) 2-
n-Butyl-6- (N-methyl-N-isobutyloxycarbonyl) amino-3-[(2 '-(tetrazole-
5-yl) biphen-4-yl) methyl] pyrido [2,2
3-d] pyrimidin-4 (3H) -one, (28) 6-
(N-Benzyl-N-butanoyl) amino-2-n-propyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H) -one, (29) 6- (N- (p-
Chloro) benzoyl-Nn-pentyl) amino-2-
n-Propyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-
d] pyrimidin-4 (3H) -one, (30) 6- (N
-N-propyl-N-isobutyloxycarbonyl) amino-2-n-propyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidine -4 (3H) -on and (3
1) 6- (N-benzoyl-N-n-pentyl) amino-3-[(2 '-(N-benzoylsulfonamido) biphen-4-yl) methyl] -2-n-propylpyrido [2,3- d] pyrimidin-4 (3H) -one,

In a third embodiment, M in formula (I) is a C atom, K is C = NR ²² , and J and L are joined together to form one N atom which is not J and 5 A compound which forms a 6-membered aromatic ring containing C atoms and is capable of substituting carbon atoms with R ⁷ , R ^8a and R ^8b . The classes and subclasses of this embodiment are the same as described above.

Specific examples of this subclass are the following compounds: (1) N-methyl 2-n-butyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl]
Pyrido [2,3-d] pyrimidine-4 (3H) -imine, (2) N-benzyl 2-n-butyl-3-[(2 '
-(Tetrazol-5-yl) biphen-4-yl) methyl] -5-methylpyrido [3,4-d] pyrimidine-
4 (3H) -imine, (3) N-phenyl-5-amino-2-n-butyl-3-[(2 '-(tetrazole-5
-Yl) biphen-4-yl) methyl] pyrido [2,3
-D] pyrimidine-4 (3H) -imine, (4) N-methyl 2-n-butyl-3-[(2 '-(tetrazole-
5-yl) biphen-4-yl) methyl] -6-isopropylpyrido [3,2-d] pyrimidin-4 (3H)-
Imine, (5) N-butyl 2-n-butyl-3-
[(2 '-(Tetrazol-5-yl) biphen-4-
Yl) methyl] -5- (N-isopropylcarbamoyl) aminopyrido [2,3-d] pyrimidine-4 (3
H) -imine, (6) N-methyl 2-n-butyl-6-
[N- (N-isopropylcarbamoyl) -N-methyl] amino-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-
d] pyrimidine-4 (3H) -imine, (7) N-propyl 2-n-butyl-6- [N- (morpholin-4-yl-carbamoyl) -N-methyl] amino-3-
[(2 '-(Tetrazol-5-yl) biphen-4-
Il) methyl] pyrido [2,3-d] pyrimidine-4
(3H) -imine, (8) N-methyl 2-n-butyl-
6- (N-isopropyloxycarbonyl-N-methyl) amino-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-
d] pyrimidine-4 (3H) -imine, (9) N-benzyl 6- (N-benzyloxycarbonyl-N-methyl) amino-2-n-butyl-3-[(2 '-(tetrazole-5- Yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H) -imine,
(10) N-methyl 3-[(2 '-(N-benzoylsulfonamido) biphen-4-yl) methyl] -2-n
-Butyl-6- (N-isopropyloxycarbonyl-
N-methyl) aminopyrido [2,3-d] pyrimidine-
4 (3H) -imine and (11) N-methyl 2-n-butyl-6- (N-isopropyloxycarbonyl-N-
Methyl) amino-3-[(2 ′-(N-trifluoromethylsulfonyl-carboxamido) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3
H) -imine

It should be noted that in naming compounds of formula (I) containing a biphenylmethyl substituent, the following two names are considered equivalent to compound (i) shown below. is there.

[Chemical formula 26] (1) 2-n-butyl-6-methyl-3-[(2'-
(Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4- (3H)-
ON or (2) 2-n-butyl-6-methyl-3-
[(2 '-(Tetrazol-5-yl) [1,1'] biphenyl-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H) -one

2,3-Disubstituted pyrido [2,3-d] or [3,4-d] or [3,2-d] or [4,3-d]
For a general review of the synthesis and reactivity of pyrimidine-4 (3H) -ones, see AR Katritzky et al.
Comprehensive Heterocyclic Chemistry, Vol. 3, p. 201 (1984) and WJ Irwin et al., Advances in Heterocyclic Chemistry, vol. 10, p. 149 (196).
9 years).

Abbreviations used in the schemes DMAP dimethylaminopyridine-OTs p-toluenesulfonate-OTf trifluoromethanesulfonate DMF dimethylformamide DBU 1,8-diazabicyclo [5,4,4]
0] Undecane FABMS Fast Atom Bombardment Mass Spectroscopy THF tetrahydrofuran tetrahydrofuran DMSO dimethylsulfoxide EtAc ethyl acetate HOAc acetic acid TFA trifluoroacetic acid

In Scheme 1, E in formula (I) is a single bond 2-
Substituted pyrido [2,3-d] or [3,2-d] or [3,4-d] or [4,3-d] pyrimidine-4 (3
H) -one is the preferred method of preparation. The appropriately substituted orthoaminopyridinecarboxylic acid 1 is treated with 2 equivalents of the required acyl chloride with triethylamine and dimethylaminopyridine (DMAP) in dimethylformamide (DMF) at 0 ° C. The mixture is then heated to 110 ° C.
After heating for an hour, excess ammonium carbonate is added. Any recovered bisamide 2 can be converted to pyrimidin-4 (3H) -one 3 by treating with base. Scheme 1

[Chemical 27]

Scheme 2 is 2,3-wherein E in formula I is a single bond.
Disubstituted pyrido [2,3-d] or [3,2-d] or [3,4-d] or [4,3-d] pyrimidine-4 (3
The general manufacturing method of H) -one (6) is illustrated. The appropriately substituted 2-alkyl-pyrimidin-4 (3H) -one 4 is replaced with sodium hydride and the appropriate alkyl halide 5 (or pseudohalide, ie Q is

[Chemical 28] And a suitable leaving group such as). The alkylating material 6 can be used to deprotect the protecting group of R ¹ or
^It can be converted to the desired compound of formula (I) by chemical conversion to ^one group. Specifically, when R ¹ is carboxy t-butyl ester or N-triphenylmethyltetrazole, treatment of 6 with HCl / MeOH or acetic acid provides the desired R ¹ carboxy or tetrazolyl functionality. When R ^{1 in} 6 is a nitrile, heating with trimethyltin azide yields the tetrazole functionality. Scheme 2

[Chemical 29] (A) If R ¹ is t-butyl or triphenylmethyl, treat with acetic acid or HCl / MeOH. (B) If R ¹ is C≡N, treat with (CH ₃ ) ₃ SnN ₃ .

Reaction scheme 3

[Chemical 30] More preferred alkylating agents (9a and 9b, reaction scheme 3)
Benzyl halides (5) containing
It can be produced as described in Nos. 53,310 and 291,969, and these references are cited. However, Ni (O) or Pd (O) catalyzed cross-linking reactions [E. Negishi, T. Takahashi and AO King Org. Synthesis 66, 67 (1987)] were used to produce the biphenyl precursor 8a. , 8b and 8c are shown in Reaction Scheme 3. As shown in Reaction Scheme 3, 4-bromotoluene (4a) is treated with t-BuLi and then a solution of ZnCl ₂ is added to obtain an organozinc compound (6a). Then, the compound (6a) is added to 7a or 7b
And in the presence of a Ni (PPh ₃ ) ₂ Cl ₂ catalyst to give the desired biphenyl compound 8a or 8b (PPh ₃ = triphenylphosphine). Similarly, 1-iodine-
2-nitro - benzene (7c) an organic zinc compound 6a and Pd (PPh _{3) 4} catalyst [a _{Cl 2 Pd (PPh 3) 2} (i-Bu) prepared by treatment with ₂ AlH (2 equivalents) of Biphenyl compound 8c when bound in the presence
To get These precursors 8a, 8b and 8c are then converted into European patent applications 253,310 and 291, 969.
In accordance with the method described in No. 1, respectively, into halomethylbiphenyl derivatives 9a, 9b and 9c.

When there is further substitution on the second phenyl ring (R ^2a, R ^2b = hydrogen), a Pd (O) -catalyzed cross-linking reaction [JK
Stille Angrew.Chem.Int.Ed.Engl. Vol. 25,
Page 508 (1986)], a preferred method for making biphenyl precursors 8d and 8e is shown in Reaction Scheme 3a. As shown in reaction scheme 3a, p-tolyltrimethyltin (6a) is combined with 7d or 7e in the presence of 5 mol% Pd (PPh ₃ ) ₄ in refluxing toluene to give the desired biphenyl compounds 8d and 8e. . Table I illustrates the synthetic use of this protocol. Compound 8d (R ² = N
O ₂ ) and 8e (R ² = NO ₂ ) can be converted into their respective chlorides by catalytic hydrogenation, diazotization and treatment with copper (I) chloride. Biphenyl fluorides that cannot be obtained by direct coupling to fluoroaryl bromides are 8d (R ² = NO ₂ ) and 8e (R ² =
It was prepared by reduction from NO ₂ ), formation of a diazonium tetrafluoroborate salt and thermal decomposition. Then these precursors 8d (R ² = NO ₂ or F or Cl) and 8e
(R ² = NO ₂ or F or Cl) in European Patent Application No. 25
3,310 and 292,969 according to the method described in halomethylbiphenyl derivatives 9d and 9 respectively.
Convert to e.

Reaction scheme 3a

[Chemical 31]

Biphenyl Synthesis Table I

[Chemical 32]

Scheme 4 illustrates an alternative method for making 2-substituted pyrido [2,3-d] pyrimidin-4 (3H) -ones [A. Dornow et al., Chem. Ber. Vol. 98, 15th
05 (1965), DM Mulrey et al., J. Or.
g. Chem. 29, 2903 (1964) and S.
G. Cottis et al., J. Org. Chem. Vol. 26, 79
Page (1961)]. The appropriately substituted 2-aminonicotinic acid amide 10 (prepared by partial hydrolysis of the corresponding nitrile) is treated with an alkyl orthoester to give the corresponding 2-substituted pyrido [2,3-d] pyrimidine-4.
(3H) -on 11 is obtained. This transformation can be used for other isomeric pyridines. Scheme 4

[Chemical 33]

Scheme 5 illustrates an alternative method for making 2-substituted pyrido [3,4-d] pyrimidin-4 (3H) -ones. The appropriately substituted 3-aminoisonicotinic acid 12 is reacted with the alkyl imidate ester 13 to give the 2-substituted pyrido [3,4-d] pyrimidin-4 (3H) -one 1
Get 4. [A. deCat et al., Chem. Abstr.
0, 12063 (1956) and W. Reed (Rie
d) et al., Ann. Chem. 707, 250 (1967).
This method can also be used for the isomeric 2-aminopyridinecarboxylic acid. Scheme 5

[Chemical 34]

Scheme 6 shows the 2,3-disubstituted pyrido [2,3-
d], [3,2-d], [4,3-d] or [3,4-
Illustrates a method for producing d] pyrimidin-4 (3H) -one. [AG Ismail, etc., J. Chem. Soc. C.
2613 (1967) and WJ Irwin (Irwi
n) et al., J. Chem. Soc. C., page 4240 (1965)].
Appropriately substituted orthoaminopyridinecarboxylic acid 15
Is a 2-substituted pyrido [2,3-d] or [3,2-d] when treated in the presence of 2 equivalents of acid chloride in pyridine or a base such as triethylamine in a solvent such as DMF.
Alternatively, [4,3-d] or [3,4-d] [1,3] oxazin-4-one 16 is obtained on heating. These can be treated with alkylamine 17 to give bisamide 18 or cyclized pyrido-pyrimidin-4 (3H) -one 19. Bisamide 18 can be converted to pyridopyrimidin-4 (3H) -one when sequentially dissolved in phosphorus oxychloride. Scheme 6

[Chemical 35]

Scheme 7 shows the 1,2-disubstituted pyrido [2,3-
d] or [3,2-d] or [3,4-d] or [4
3 illustrates the preparation of 3-d] pyrimidin-4 (1H) -one 20. The appropriately substituted orthoaminopyridine nitrile 21 can be acylated with the required acid chloride. The resulting amide 22 can be alkylated with a suitable alkyl halide (or pseudohalide) 23 in the presence of sodium hydride. The resulting tertiary amide 24 is then rearranged / cyclized using basic hydrogen peroxide. Scheme 7

[Chemical 36]

Scheme 8 shows 1,2-disubstituted pyrido [2,3-
d] A method for producing pyrimidin-4 (1H) -one 25 is exemplified. The appropriately substituted 2-alkylamino-3-cyanopyridine 26 can be hydrolyzed to the acid salt 27. Reaction with oxalyl chloride yields isotin 28. 1, by the condensation of isotin and imidate ester
2-disubstituted pyrido [2,3-d] pyrimidine-4 (1
H) On 25 is obtained [DGM Coppala et al., J.
Het. Chem. Vol. 22, p. 193 (1985)]. Using thioamidine gives 1-alkyl-2-aminoalkylpyrido [2,3-d] pyrimidin-4 (1H) -one 29. This chemistry is available for other isomeric pyridines. Scheme 8

[Chemical 37]

Scheme 9 illustrates a method for preparing the 2,3-disubstituted pyrido [2,3-d] pyrimidin-4 (1H) -one 30 (E = O, S or N). Suitable pyrimidine-2,
3-dione or its derivative 31 and aminoaldehyde 32
The condensation of pyrido [2,3-d] pyrimidinedione 3
Get 3. [E. Stark et al., Tetrahedron, Vol. 29, p. 2209 (1973)]. Alkylation of the heterocycle with an alkyl halide (or pseudohalide) in the presence of sodium hydride gives the 2-substituted pyrido [2,3-d] pyrimidin-4 (1H) -one 30. [A. Srinivason et al., J. Org. Chem.
Volume 43, page 828 (1978)]. Alkylation of 30 in DMF as described in Figure 2 gives the desired 2,3
-Disubstituted pyrido [2,3-d] pyrimidine-4 (3H)
Get on (I) Scheme 9

[Chemical 38]

Scheme 10 is a 2,3-disubstituted pyrido [3,4-d] linked from an orthoaminopyridinecarboxylic acid 35 with an imidate ester (E = O, N, S or C).
A method for making pyrimidin-4 (3H) -one is described. The resulting heterocycle is then alkylated by conventional methods to give the desired 2,3-disubstituted pyrido [3,4-d] pyrimidin-4 (3H) -one 34. Figure 10

[Chemical Formula 39]

Scheme 11 is an N-alkyl, 2,3-disubstituted pyrido [4,3-d] or [3,4-d] or [2,3
The method for producing -d] or [3,2-d] pyridine-4 (3H) -imine 36 is illustrated. 2,3 properly protected
A disubstituted pyrido [4,3-d], [3,4-d],
[2,3-d] or [3,2-d] pyrimidine-4 (3
H) -one 37 is treated with Rowesson's reagent to give the corresponding thione 38. Condensation of thione with amines in a suitable solvent (eg benzene, DMF) at elevated temperature gives the desired heterocycle 36 [T. Zimaitg et al., Indian J. Che.
m. 15B. 750-751 (1977) and L. Legrand et al., Bull. Chem. Soc. Fr. 1411 (1975)]. Scheme 11

[Chemical 40]

R¹ Is -CONHSO₂ R^{twenty two}(R^{twenty two}= Al
A compound of formula I which is
The product is the corresponding carboxylic acid derivative as shown in Scheme 12.
It can be manufactured from 39. As described in Scheme 2
The carboxylic acid 39 obtained is refluxed with thionyl chloride or, preferably, a salt.
Oxalyl chloride and catalytic amount of dimethylformamide at low temperature
It is converted to the corresponding acid chloride by treatment at
[A. W. Burgstahle
r), L.S. O. Weigel and C.I. G. Shaev
Shaefer, Synthesis, p. 767 (1976)]. Next
R in acid chloride ^{twenty two}SO₂ NH₂ With alkali metal salt of
To produce the desired acylsulfonamide 40.
You can In addition, these acyl sulfonamides
Boronic acid to N, N-diphenylcarbamoyl anhydride intermediate
It can be manufactured using the body [F. J. Brown (B
rown) et al., European Patent Application No. 199543, K. et al. L. Shi
Shepard and W. Halczenko
J. Het. Chem. 16: 321 (1979)].
Preferably the carboxylic acid is converted to an acyl-imidazole intermediate.
Then the appropriate aryl or alkyl sulphate
With honamide and diazabicycloundecane (DBU)
Treatment to give the desired acylsulfonamide 43 [J.
T. Drummond and G.M. Johnson
n), Tetrahedron Lett. 29, 1653.
(1988)].

Compounds of formula I wherein R ¹ is SO ₂ NHCOR ²² can be prepared as shown in scheme 13.
Nitro compound eg 8c (prepared as described in Scheme 3)
Can be reduced to the corresponding amino compound and converted to an aromatic diazonium chloride salt, which is then reacted with sulfur dioxide in the presence of a copper (II) salt to form the corresponding arylsulfonyl chloride 41. [H. Meerwein, G.W. Dittm
ar), R.A. Gollner, K. Hafner
r), F.I. Mensch and O.M. Steifot
Ort), Chem. Ber. 90, 841 (1957).
Year), A. J. Prinsen and H.P. Cerfontain, Rekyuail Volume 84, page 24 (1965), E.I. E. Gilbert, Synthesis, page 3 (1969), incorporated herein by reference]. Sulfonyl chloride is treated with ammonia in an aqueous solution or an inert organic solvent [F. H. Bergheim and W.M. Baker, J. Amer. Chem. Soc. Vol. 66 (1944)
1459] or dry powder ammonium carbonate [E. H. Huntress and J. S. Autenrieth, J. Amer. Chem. Soc. Vol. 63 (19
41), page 3446, E.I. H. Huntless and F.F.
H. Curtain (Carten), J. Amer. Chem. Soc. Volume 62,
(1940) p. 511] to form sulfonamide 42. The sulfonamide can then be suitably reacted with triphenylmethyl chloride and triethylamine and protected with a triphenylmethyl group to give 43. Benzyl bromide 44 can be prepared from sulfonamide 43 as shown in Scheme 16 and then reacted with an alkali metal salt of a suitable heterocyclic compound to form key sulfonamide 45. The sulfonamide 45 can also be prepared from the aromatic sulfonyl chloride 48 by treatment with ammonia. Additionally 48 can be prepared from an arylamine 47 as shown in Scheme 14. 48
Can be reacted with the appropriate acyl chloride (or acyl-imidazole or other acylating agent) to produce the desired acyl sulfonamide 46.

Compounds having R ¹ as --SO ₂ NHR ²² (R ²² is heteroaryl) are prepared by reacting an aromatic sulfonyl chloride 48 with a suitable heteroaryl amine to give 49 as shown in Scheme 14. It can be manufactured. The sulfonyl chloride 48 can be prepared using the same chemistry as shown above. Sulfonyl chloride 48 can be a suitable intermediate for the synthesis of this type of compound. Aromatic sulfonyl chlorides may also be prepared by adding the sodium salt of aromatic sulfonic acid to PCl ₅ or P
It can be produced by reacting with OCl ₃ [C. M. Suter, The Organic Chemistry of Sulfa, John Willie & Sons, p. 459 (1944)]. Aromatic sulfonic acid precursors can be prepared by chlorosulfonation of aromatic rings with chlorosulfonic acid [E. H. Huntless and F.F. H. Curtain, J. Amer. Chem. Soc. No. 62
Vol. 511 (1940)].

Scheme 12

[Chemical 41] One of A, B, C, D is N and the other is C. * Alternative method a) (i) SOCl ₂ , reflux (ii) R ²² SO ₂ NH ^- M ⁺ (M is Na or Li) b) (i) (COCl) ₂ -DMF, −20 ° C. (ii) ^{_{R 22 SO 2 NH - M +}} c) (i) N (N, N- diphenylcarbamoyl) pyridinium chloride / aqueous _{^{NaOH (ii) R 22 SO 2}} NH - M +

Scheme 13

[Chemical 42] Scheme 13 (continued) a. _{(I) H 2 / Pd-} c (ii) NaNO 2 -HCl (iii) SO 2, AcOH, CuCl 2 b. NH ₃ or _{(NH 4) 2 CO 3 c} . (C ₆ H ₅ ) ₃ CCl, Et ₃ N, CH ₂ Cl
₂ , 25 ° C d. N-bromosuccinimide e. R ²² COCl or R ²² CO-Im or other acylating agent

Scheme 14

[Chemical 43]

Scheme 15

[Chemical 44] a. (I) t-BuLi / ether, -78 ° C (ii) Me ₃ SnCl b. (I) NaNO ₂ / HCl (ii) SO ₂ , CuCl ₂ C.I. Pd (PPh ₃ ) ₄ , toluene, reflux or (PPh ₃ ) ₂ PdCl ₂ , DMF, 90 ° C.

Biaryl sulfonamides 50 and 51
(Depicted as 43 in Scheme 13) can also be prepared using the palladium (O) -catalyzed cross-linking reaction of a suitable aryl-organotin precursor as shown in Scheme 15 [J. K. Stille, Pure Appl. Chem. 57th
Vol. 1771 (1985), T.S. R. Baerie
(Baiely), Tetrahedron Lett. 27, 4407.
Page (1986), D.M. A. Widowson and Y.
Z. Zhang, Tetrahedron Volume 42, 21
Page 11 (1986)]. Organotin compound 52 obtained from aromatic precursor 53 [S. M. Mail Rain (Moerlei
n), J. Organo Metallic Chem. Volume 319, Volume 29
Page (1987)] with aryl sulfonamides 54 and 55 and Pd (PPh ₃ ) ₄ or (PPh ₃ ) as a catalyst.
Coupling with ₂ PdCl ₂ can give biaryl sulfonamides 50 and 51. Similarly, benzyl bromide 56 also contains Pd (O) as shown in Scheme 16.
It can be prepared from a suitable organotin compound precursor 57 using a catalytic cross-linking reaction.

Scheme 16

[Chemical formula 45] a. t-BuMe ₂ Si-Cl / imidazole, DMF b. t-BuLi, -78 ℃, Me 3 SnCl c. Tetrabutylammonium fluoride d. CBr ₄ / Ph ₃ P

Scheme 17

[Chemical formula 46] Scheme 17 (continued) a. (I) EtOCOCl / Et ₃ N, THF, 0 ° C. (ii) NaBH ₄ (iii) CCl ₄ or CBr ₄ / PPh ₃ b. AcSK c. SO ₂ Cl ₂ d. Cl ₂ , AcOH, H ₂ O or (i) SO ₂ Cl ₂ (ii) oxidation e. R ^y NH ₂ or (i) NH ₃ (ii) acylation f. Mg

R ¹ = CH ₂ SO ₂ NHCOR ²² and -C
Compounds having H ₂ SO ₂ NHR ²² can be prepared as shown in Scheme 17. Key precursor aryl-
Methanesulfonyl chloride 58 is prepared from the reaction of the corresponding benzyl chloride 60 with arylmethylmagnesium chloride 59 obtained from magnesium or by oxidation of arylmethyl thioacetate 61 (prepared from benzyl bromide 62) with chlorine in the presence of trace amounts of water. Can [Bagnay and Dransch]
Chem. Ber. 93, 784 (1960).
Year)]. Also, aryl-methyl thioacetate 61 can be oxidized with sulfuryl chloride in the presence of acetic anhydride to produce arylmethylsulfinyl chloride [S. Thea and G. Cevasco, Tet.
Lett. 28, 5193 (1987)], which is further oxidized with a suitable oxidizing agent to give sulfonyl chloride 58.
Can be obtained. Compounds 63 and 64 can be obtained by reacting the sulfonyl chloride 58 with the appropriate amine.

The compound (R ¹ = -NHSO ₂ NHR ²² ) can be prepared by reacting the appropriate primary amine with sulfamide 65 as described in Scheme 18 [S. D.
McDermott and W.M. J. Spiran (Spi
Llane), Synthesis, page 192 (1983)]. Compound 6
5 can be obtained from the corresponding Nt-butylsulfamide 66 after treatment with trifluoroacetic anhydride [J.
D. Catt and W. L. Matier, J.Org.
Chem. 39, 566 (1974)]. Nt
-Butylsulfamide 66 is an aromatic amine 67 (Scheme 1
(Prepared as described above) with t-butylsulfamoyl chloride [W. L. Mathia,
W. T. Comer and D.C. Deitchm
an), J. Med. Chem. Vol. 15, p. 538 (1972)
Year)]. Scheme 18

[Chemical 47]

Further functionalization of compounds of formula 1 wherein R ^8a or R ^8b is nitro can be obtained by the following route (Scheme 19). The nitro group of 68 can be reduced with hydrogen over palladium / carbon to the amine 69. The amine can then be acylated with an acid chloride to give the amide under basic conditions. Acylation of amines with chloroformates works well in the presence of sodium hydride to produce the anilinium anion. This anion reacts rapidly with chloroformate to give carbamate 7
Get 0. The carbamate can be separated and then deprotonated with lithium hexaethyldisilazide and alkylated to give the N, N-dialkylated carbamate 71. This method can also be carried out in one pot by first generating the anilinium anion in advance, acylating it, then deprotonating at this position and alkylating with the R ⁴ iodide group to give 71. Amine 69
Reacts slowly with isocyanate to give urea 72.
Tri-substituted urea 73 can be prepared from benzyl carbamate 70 (R ²² = benzyl) by treatment with a magnesium salt of a secondary amine. Tri-substituted urea is deprotonated with lithium hexamethyldisilazide to give iodide R
It can be N-alkylated by alkylation with ⁴ to give 74. Furthermore, amines can be derivatized or converted to other groups by chemical methods well known to those skilled in the art.

Scheme 19

[Chemical 48] Scheme 19 (continued)

[Chemical 49]

It will be appreciated by those skilled in the art that the protecting groups used in these syntheses are chosen to be compatible with the subsequent reaction conditions. Eventually they are removed to yield the active compound of formula (I). Specifically, R ¹ as a carboxyl is often protected as a t-butyl ester and removed in the last step by treatment with trifluoroacetic acid. The overnight use of aqueous acetic acid is preferred for removing the trityl protecting group and liberating the R ¹ tetrazole group.

The compounds of the present invention form salts with various inorganic and organic acids and bases that are also within the scope of the invention. Such salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salt, N-methyl-D-glucamine, amino acids. Examples include salts with arginine and lysine. Also organic and inorganic acids such as HCl, HBr, H ₂ S
It is also possible to prepare salts with O ₄ , H ₃ PO ₄ , methane-sulphonic acid, toluenesulphonic acid, maleic acid, fumaric acid, camphorsulphonic acid. Non-toxic, physiologically acceptable salts are preferred, eg for separating or purifying the product, but other salts are useful. The salt is obtained by dissolving the free acid or free base form of the product in a solvent or medium in which one or more equivalents of a suitable base or acid and the salt are insoluble, or in a solvent such as water which is subsequently removed under vacuum or by lyophilization. It can be formed by a conventional method such as reacting or exchanging an existing salt cation with another ion by a suitable ion exchange resin.

Angiotensin II (AII) is a powerful arterial vasoconstrictor, which exerts its action by interacting with a specific receptor existing on the cell membrane. The compounds described in this invention act as competitive antagonists of AII at the receptor. The following two ligand-receptor binding assays were established to identify AII antagonists and quantify their efficacy in vitro.

Receptor binding using rabbit aortic membrane preparations
Coalescence Assay Three frozen rabbit aortas (obtained from Perforys Biologicals) were added to 5 mM Tris-0.25M sucrose,
Suspended in pH 7.4 buffer (50 ml), homogenized and then centrifuged. Filter this mixture through cheesecloth,
The supernatant was centrifuged for 30 minutes at 20.000 rpm at 4 ° C. The precipitate thus obtained was resuspended in 30 ml of 50 mM Tris-5 mM MgCl ₂ buffer containing 0.2% bovine serum albumin and 0.2 mg / ml bacitracin, and the suspension was used for 100 test tubes. Samples tested for screening were run in duplicate. Membrane preparation sample (0.25
ml) ¹²⁵ I-Sar ¹ Ile ⁸ -Angiotensin II
[Obtained from New England Nuclea] (10 μl,
20.000 cpm) was added with or without the test sample and the mixture incubated at 37 ° C for 90 minutes. The mixture was then ice-cold 50 mM Tris-0.9% NaCl,
Dilute with pH 7.4 (4 ml) and use a glass fiber filter (G
F / B Whatman 2.4 ″ diameter). Immerse filter in scintillation reaction mixture (10 ml),
Radioactivity was counted using a Packard 2660 Tricarb liquid scintillation counter. The inhibitory concentration (IC ₅₀ ) of the potential AII antagonist that gives 50% displacement of all ¹²⁵ I-Sar ¹ Ile ⁸ -angiotensin II bound specifically was determined as AII.
It is presented as a measure of efficacy of compounds such as antagonists.

Receptor Assay Using Bovine Adrenal Cortex Preparation Bovine adrenal cortex was selected as the AII receptor source. The weighed tissue (requires 0.1 g for 100 assay tubes) was suspended in Tris-HCl (50 mM) pH 7.7 buffer and homogenized. The homogenate was centrifuged at 20.000 rpm for 15 minutes. The supernatant is discarded and the sediment is buffered [phenylmethanesulfonyl fluoride (PMSF) (0.1 mM)
Containing Na ₂ HPO ₄ (10 mM) -NaCl (12
0 mM) -Disodium EDTA (5 mM)]. (Compounds are generally screened in duplicate experiments). To the membrane preparation (0.5 ml) was added 3H-angiotensin II (50 mM) (10 μl) with or without the test sample and the mixture was allowed to stand at 37 ° C.
And incubated for 1 hour. The mixture was then diluted with Tris buffer (4 ml) and filtered through a glass fiber filter (GF / B Whatman 2.4 ″ diameter). The filter was immersed in scintillation reaction mixture (10 ml) and Packard 2660 Tricarb liquid scintillation counter. The radioactivity was counted using an inhibitory concentration (IC ₅₀ ) of a potential AII antagonist that results in 50% displacement of specifically bound all ³ H-angiotensin II, a measure of the potency of a compound such as an AII antagonist. Indicated as.

Representative compounds of the present invention were evaluated using the methods described above and were found to exhibit activity of at least IC ₅₀ <50 μM, which makes the compounds of the present invention useful as effective AII antagonists. Was proved and confirmed.

The potential hypotensive effects of the compounds described in this invention can be evaluated using the methods described below. Male Charles Reverse Plug-Dawley rat (300-375g) was anesthetized with methohexital (Brevital, 50mg / kg, ip) and PE205 was placed on the trachea.
The tube was cannulated. A stainless steel puncture needle (1.5 mm thick, 150 mm long) was inserted into the orbit and spinal column of the right eye. The rat was immediately subjected to Harvard Roent ventilator (speed-60 strokes per minute, volume-weight 1
1.1 cc per 00 g). Ligate the right carotid artery,
Both left and right vagus nerves were dissected, the left carotid artery was cannulated with PE50 tubing for drug administration, and body temperature was maintained at 37 ° C by a thermostatically controlled heating pad input from a rectal temperature probe. Next, atropine (1mg / kg
15 minutes later (intravascularly), propranolol (1 mg / kg intravascularly) was administered. After 30 minutes, the antagonist of formula (I) was administered intravenously or orally. Angiotensin II is then typically administered at 5, 10, 15, 30, 45 and 60 minute intervals,
All test compounds alone showed activity after 30 minutes. Changes in mean arterial blood pressure were recorded for each angiotensin II challenge and the% inhibition of angiotensin II response was calculated.

The compounds of the invention are therefore useful in treating hypertension. These compounds are also effective in treating acute and chronic congestive heart failure. These compounds are also secondary hyperaldosteronism, primary and secondary pulmonary hyperaldosteronism, primary and secondary pulmonary hypertension, diabetic kidney disease, glomerulonephritis, scleroderma, glomerulosclerosis, For treatment of primary renal disease proteinuria, end stage renal disease, renal failure such as renal transplant treatment, renal vascular hypertension, left ventricular dysfunction, diabetic retinopathy and migraine, Raynaud's disease, luminal hyperplasia Can be expected to minimize the atherosclerotic process. The application of the compounds of the invention to these and similar diseases will be apparent to those of skill in the art.

The compounds of the present invention are also useful for treating elevated intraocular pressure and are typical of pharmaceutical formulations such as tablets, capsules, injectables and solutions, ointments, inserts, gels and the like. The ophthalmic formulation can be administered to patients in need of such treatment. Pharmaceutical formulations prepared to treat intraocular pressure typically contain about 0.
1 to 15% by weight, preferably 0.5 to 2% by weight.

For the treatment of hypertension and the clinical conditions mentioned above, the compounds according to the invention are tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration. It can be used as a composition such as a suspension. The compounds of the present invention can be administered to patients (animals and humans) in need of such treatment at dosages that provide optimal pharmaceutical efficacy. The dosage range will generally depend on the type and severity of the illness, the patient's weight, the particular diet followed by the patient, co-medication and other factors which will be appreciated by those of ordinary skill in the art, although the dosage range will generally depend on the patient. The daily dose is about 1 to 1000 mg per person and can be administered once or several times. Preferably, the dosage range is about 2.5 to 250 mg per patient per day, more preferably about 2.5 to 75 mg per patient per day.

The compounds of the present invention can also be administered in combination with other antihypertensive and / or diuretic and / or angiotensin converting enzyme inhibitors and / or calcium channel blockers. Specifically, the compounds of the present invention are amiloride, atenolol, bendroflumethiazide, chlorothalidon, chlorothiazide, clonidine, cryptenamin acetate and cryptenamin tannate, deserpidine, diazoxide, guanetidene sulfate, hydralazine hydrochloride, hydrochlorothiazide. , Metrazone, metoprolol, tartrate, methylclothiazide, methyldopa, methyldopeto hydrochloride,
Minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, lauolphia serpentina, resinnamine, reserpine, sodium nitroprusside, spironolactone, timolol maleate, trichlormethiazide, trimethofancamsylate, benzthiazide, quinetazone, ticrinafane, Triamterene, acetazolamide, aminophylline,
Cyclothiazide, ethacrynic acid, furosemide, meretoxylin procaine, sodium ethacrynate, captopril, delapril hydrochloride, enalapril, enalapril rat, fosinopril sodium, lisinopril, pentopril, quinapril hydrochloride, ramapril, teprotide, zofenopril. It can be administered in combination with calcium, diflucinal, diltiazem, felodipine, nicardipine, nifedipine, nildipine, nimodipine, nisoldipine, nitrendipine, etc., and mixtures and combinations thereof.

Typically, the individual daily doses of these combinations will range from about 1/5 of the minimum recommended clinical dose to the disease to the maximum recommended dose for the disease when they are administered alone. Can be in the range of.

The specific description of these concomitant agents is as follows:
One of the angiotensin II antagonists of the present invention which is clinically effective at 2.5 to 250 mg / day was given in the following daily dose range: Hydrochlorothiazide (15-200 m
g), chlorothiazide (125-2000 mg), ethacrynic acid (15-200 mg), amiloride (5-20 m)
g), furosemide (5-80mg), propranol (2
0-480mg), timolol maleate (5-60m)
g), methyldopa (65-2000 mg), felodipine (5-60 mg), nifedipine (5-60 mg) and nitrendipine (5-60 mg) can be effectively mixed at a level of 0.5-250 mg daily. Furthermore, hydrochlorothiazide (15-200 mg) and amiloride (5-20 m)
g) and an angiotensin II antagonist of the present invention (3 to 200 m
g) or hydrochlorothiazide (15-200 mg), timolol maleate (5-60 mg), the angiotensin II antagonist of the present invention (0.5-250 mg) or hydrochlorothiazide (15-200 mg) and nifedipine (5-6).
0 mg) and an angiotensin II antagonist of the present invention (0.5-
The 250 mg) triple combination is an effective combination for controlling blood pressure in hypertensive patients. Of course, these dosage ranges can be adjusted on a unit-by-unit basis as necessary to provide the daily dose, as indicated above, depending on the type and severity of the illness, the weight of the patient, the particular diet and other factors. different.

Typically these combinations will be formulated into the pharmaceutical compositions described below. About 1 to 1 compounds of formula (I) or mixtures of compounds or physiologically usable salts
00 mg is formulated as a unit dosage form required by the accepted pharmaceutical practice with physiologically usable agents, carriers, excipients, binders, preservatives, stabilizers, flavors and the like. The amount of active substance in these compositions or preparations is such that a suitable dosage in the indicated range is obtained.

Specific examples of auxiliaries which can be mixed with tablets, capsules and the like include the following binders such as gum tragacanth, gum arabic, corn starch or gelatin, excipients such as microcrystalline cellulose, disintegrating agents such as corn starch, gel. Pregelatinized starch, alginic acid and the like, lubricants such as magnesium stearate, sweeteners such as sucrose, lactose or saccharin, flavoring agents such as peppermint, red oil or cherry. When the dosage unit form is a capsule, it can contain, in addition to the above types, liquid carriers such as fatty oils. Various other materials can be present as coatings or otherwise to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a cherry or orange flavor.

Sterile compositions for injection consist of the active substance in water for injection,
It may be dissolved or suspended in a natural vegetable oil such as sesame oil, coconut oil, peanut oil, cottonseed oil, or an excipient such as a synthetic fat excipient such as ethyl oleate and formulated according to a usual pharmaceutical practice. A buffering agent, a preservative, an antioxidant and the like can be mixed if necessary.

The following examples illustrate the preparation of compounds of formula (I) and their incorporation into pharmaceutical compositions, but limit the invention set out in the claims appended hereto. Should not be construed as doing. All ¹ H NMR spectra were recorded on a Varian XL-300 Fourier Transform spectrometer. Chemical shifts were recorded as the low field from tetramethylsilane (part for 1 million). The mass spectrum is Rahway. Obtained from Merck & Co. Mass Spectrometer, New Jersey. T for analysis
LC is E. M. UV was visible on Merck pre-coated silica plates (0.25 mm on glass, Kieselgel 60F ₂₅₄ ). All chromatography is E. M. Performed on Merck silica gel. All reactions were performed under an atmosphere of dry nitrogen and under conditions standard to those skilled in the art. In the following examples, Examples 7 and 8 are reference examples.

Preparation of Intermediate 2-Cyano-4'-methylbiphenyl A solution of p-bromotoluene (30g) in dry ether (150ml) at -78 ° C in t-BuLi solution in pentane (1.7M) ( 210 ml) using a dropping funnel for 1.5
Gradually added over time. The bath was then removed and the mixture was stirred at room temperature for a further 2 hours. The contents of the flask were treated with ZnCl ₂ (1M) in ether (180 ml) and dry THF (3
60 ml) of the premixed solution was added slowly (using a cannula) at room temperature. The mixture was stirred at this temperature for 2 hours and then the slurry was treated with 2- in dry THF (300 ml).
Bromobenzonitrile (21.3 g) and NiCl ₂ (P
h ₃ P) ₂ (2.1 g) was added to the solution. After stirring overnight (18 hours) at room temperature, the mixture was ice-cooled with stirring.
Slowly poured into NH Cl (1500 ml). The organic layer was separated and the aqueous phase was extracted with ether (3 x 300 ml). The combined organic layers are washed with water, brine, then M
It was dried over gSO ₄ . The solvent was removed to give the crude product as a semi-solid (34g). This material was purified on a silica gel flash column eluting with ethyl acetate-hexane (1:12) to give the desired nitrile as a low melting solid (28 g, 88%). NMR (CDCl _3): 2.42
(S, 3H), 7.2-7.8 (m, 8H); FAB-
MS: m / z 194 (M ⁺⁺ 1). Obtained as a solid (28 g, 88%). NMR (CDCl _3): 2.42
(S, 3H), 7.2-7.8 (m, 8H); FAB-
MS: m / z 194 (M ⁺⁺ 1).

Trimethylstannyl azide To a concentrated solution of NaN ₃ (1.2 kg, 18.5 mol) in water (3 liters) was added a solution of trimethyltin chloride (600 g, 3 mol) in dioxane (400 ml) in three portions. And added with vigorous stirring. A precipitate formed instantaneously. After stirring overnight at room temperature, the mixture was filtered. The residue was washed with water, suctioned and then dried in vacuo over P ₂ O ₅ . Yield 541 g (88%), m.p. p. 120-122 ° C

5- [2- (4′-methylbiphenyl)]
Trimethyltin azide (525 g, 2.55 mol) was added at room temperature to a solution of 2-cyano-4'-methylbiphenyl (390 g, 2.02 mol) in tetrazole toluene (2.3 liter). The mixture is refluxed for 24 hours, cooled to room temperature,
It was filtered, washed with toluene and suction dried with a funnel. The precipitate is resuspended in toluene (3.5 liters) and THF (250
ml) was added. Anhydrous HCl was bubbled in at room temperature at a moderate rate to give a clear solution (45 minutes). The addition of HCl gas was continued for another 20 minutes with stirring and a white precipitate formed. The reaction mixture was stirred overnight. The solid product was filtered, washed with toluene then ether and then dried under vacuum (250 g). (Yield 53%) m. p. 152-
154 ° C; ¹ H-NMR (CDCl ₃ ): 2.40.
(S, 3H), 7.19 (dd, 1H), 7.55
(M, 2H), 8.25 (dd, 1H). (M, 2H), 8.25 (dd, 1H).

N-triphenylmethyl-5- [2-
(4'-methylbiphenyl)] Tetorazo Le CH ₂ Cl
_In a cloudy solution of 250 g (1.06 mol) of 5- [2- (4'-methylbiphenyl)] tetrazole in ₂ (4 liters) triphenylmethyl chloride (310 g, 1.11).
Mol) was added at room temperature. The reaction mixture was stirred and triethylamine (190 ml, 138 g, 1.36 mol) was added dropwise. After the addition, the mixture was stirred under reflux for 90 minutes. The solution was cooled to room temperature, washed with water (2 x 1 liter), dried over MgSO ₄ , filtered through a silica gel plug,
Concentrate to a solid by rotary evaporation. This was crystallized from toluene to give the product as an off-white solid (4
25 g, 84%). m. p. 166-168 ° C, ¹ H-
_{NMR (CDCl 3): 2.28 (} s, 3H), 6.9
-7.05 (m, 10H), 7.2-7.5 (m, 12
H), 7.9 (dd, 1H). 5 (m, 12H), 7.9 (dd, 1H).

N-triphenylmethyl-5- [2-
Solution of (4'-bromomethyl biphenyl)] Tet Razoru CCl ₄ (4.0 liters) in N- triphenylmethyl-5- [2- (4'-methylbiphenyl)] tetrazole (425 g, of 0.89 mol) Newly opened N
9 mol) and dibenzoyl peroxide (22 g, 0.0
89 mol) was added. The mixture was refluxed for 2 hours, cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give a thick oil. Ether (2.0 liters) was added to this oil to give a clear solution which was crystallized and filtered to give a white solid (367g, 74%). m. p. 137-
^{139.5 ℃, 1 H-NMR (} CDCl 3): 4.38
(S, 2H), 6.9-8.0 (m, 23H).

2-alkyl-pyridopyrimidine-4 (1
H) -on production

Example 1 2-n-butylpyrido [2,3-d] pyri
Midin-4 (1H) -one 7.5 g (75 mmol) triethylamine in a suspension of 3.5 g (25 mmol) 2-aminonicotinic acid in 15 ml dry DMF at room temperature and then 6.27 g valeryl chloride.
(52 mmol) was added. This mixture is heated to 120 ° C for 2
Sun) showed that the starting material had converted to the less polar benzoxazine. 10.0 g NH ₄ CO ₃ was carefully added to the hot reaction mixture. The mixture was cooled and concentrated in vacuo. The residue was dissolved in 100 ml EtOAc and 50 ml water. The phases were separated and the aqueous phase re-extracted twice with 25 ml EtAc each. The combined organic phases were washed with saturated NH ₄ CO ₃ (25 ml).
Wash twice with each) and brine (once with 25 ml) and wash with MgS
Dry with O ₄ . The solution was filtered and concentrated in vacuo.
The residue was converted to 95: 5: 0.01 CHCl ₃ : MeOH:
To give a brown solid 0.336g was purified by flash chromatography on silica gel eluting with NH ₄ OH. Dissolve the solid in 6 ml of 0.5 M NaOH solution to 10
Heat to 0 ° C. for 1 hour. The solution is cooled to room temperature and 2M
Acidification with HCl gave a white precipitate 0.18 g (0.8 mmol). ¹ H-NMR (CDCl ₃ ): 0.97
(T, 3H, J = 7.38 Hz), 1.47 (m, 2
H), 1.90 (m, 2H), 2.82 (t, 2H,
7.5 Hz), 5.1 (bs, 1H), 7.43 (d
d, 1H, J = 4.4, 7.8 Hz, 8.58 (d
d, 1H, J = 1.8, 7.8 Hz), 9.01 (m,
1H).

[0078]

Example 2 2-n-butylpyrido [3,2-d] pyri
Midin-4 (1H) -one 3-aminopyridine-2-carboxylic acid 1.5 g (11.
7 mmol) and in the same manner as in Example 1 above. The crude product was recrystallized from EtAc / hexane to give 0.79 g (3.89 mmol) of a pale yellow solid, yield 33.
%. ¹ H-NMR (CDCl ₃ ): 0.94 (t, 3
H, J = 7.33 Hz), 1.45 (m, 2H), 1.
84 (m, 2H), 2.89 (t, 2H, J = 7.5H
z), 7.67 (dd, 1H, J = 4.29, 8.36)
Hz), 8.04 (d, 1H, J = 7.05 Hz),
8.84 (d, 1H, J = 3.04Hz), 12.38
(Bs, 1H).

[0079]

Example 3 2-n-butylpyrido [3,4-d] pyri
Midin-4 (1H) -one 3-amino-pyridine-4-carboxylic acid 10 g (7.2
The same method as in Example 1 above. Treatment of the intermediate bisamide with sodium hydroxide, then pH 4-5
Acidification to give 0.39 g (1.9 mmol) of a pale yellow solid, yield 26%. ¹ H-NMR (CD ₃ O
D): 0.89 (t, 3H, J = 7.3 Hz), 1.4
7 (m, 2H), 1.72 (m, 2H), 2.61
(T, 2H, J = 7.6 Hz), 7.93 (d, 1H,
J = 5.1 Hz), 8.49 (d, 1H, J = 5.1H)
z), 8.87 (s, 1H). z), 8.87 (s, 1H).

2,3-dialkyl-pyridopyrimidine-
Production of 4 (3H) -one

Example 4 2-n-butyl-3- (2 '-(N-triphenylmethyl-tetrazol-5-yl) biphen-
4-yl) methylpyrido [2,3-d] pyrimidin-4
(3 H) -on dry DMF in a suspension of 80% NaH / oil 16.5 mg (0.55 mmol) in 0.5 ml dry DMF.
2-butylpyrido [2,3-d] pyrimidine-4 (1
A solution of 0.1 g (5.0 mmol) H) -one was added at 0 ° C. N in 0.5 ml DMF after hydrogen evolution is completed
A solution of 0.25 g (0.48 mmol) of -triphenylmethyl-5- [2- (4'-bromomethylbiphenyl)] tetrazole was added. After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo and partitioned between 10 ml water and 10 ml EtAc. The phases were separated and the aqueous phase was reextracted with EtAc (5
3 times for each ml). The combined organic phases are washed with brine (1
(1 x 0 ml) and dried over MgSO ₄ . The solution was filtered, concentrated in vacuo and the residue was purified by flash chromatography on silica gel eluting with 40% EtAc / Hexanes to give 0.058 g (0.09 mmol) of product as an oil. ¹ H-NMR (CDCl
₃ ): 0.89 (t, 3H), 1.37 (m, 2H),
(T, 2H), 5.30 (s, 2H), 6.95-7.
0 (m, 8H), 7.12 (d, 2H), 7.20-
7.38 (m, 10H), 7.40-7.52 (m, 3
H), 7.903 (dd, 1H), 8.63 (dd, 1)
H), 9.00 (d, 1H). (D, 1H).

[0081]

Example 5 2-n-butyl-3- (2 '-(N-triphenylmethyl-tetrazol-5-yl) biphen-
4-yl) methylpyrido [3,2-d] pyrimidine-4
A solution of 0.1 g (0.5 mmol) of 2-n-butylpyrido [3,2-d] pyrimidin-4 (1H) -one dissolved in 1 ml of dry DMF at 0 ° C. under (3 H) -one N _2. 0.5 ml of a 1M solution of lithium hexamethyldisilazane in toluene (0.
52 mmol) was added. Stir this solution for 30 minutes,
It was then treated with a solution of 0.29 g (0.57 mmol) N-triphenylmethyl-5- [2- (4'-bromomethylbiphenyl)] tetrazole in 1 ml dry DMF. The solution was warmed to room temperature, stirred overnight and concentrated in vacuo. The residue was partitioned between 10 ml EtAc and 10 ml water. The phases were separated and the aqueous phase was extracted with EtAc (3 x 5 ml).
Times). The combined organic extracts were washed with water (2 x 5 ml) and brine (1 x 10 ml) and dried over MgSO ₄ .
The solution was filtered and concentrated in vacuo. 60% E of the residue
Purify by flash chromatography on silica gel eluting with tAc / hexane to give a yellow oil 0.169.
g (0.24 mmol) was obtained. ¹ H-NMR (CDC
0.88 (t, 3H, J = 7.4Hz), 1.32
(M, 2H), 1.71 (m, 2H), 2.67 (t,
2H, J = 7.5 Hz), 5.34 (bs, 2H),
6.90 (m, 4H), 7.00 and 7.08 (AB,
4H, J = 8.2 Hz), 7.21-7.35 (m, 1
2), 7.45 (m, 2H), 7.67 (dd, 1H,
J = 4.17, 8.4 Hz), 7.93 (m, 1H),
8.00 (d, 1H, J = 8.3 Hz), 8.86 (d
d, 1H, J = 1.5, 4.4 Hz). z).

[0082]

Example 6 2-n-Butyl-3-[(2 '-(N-triphenylmethyl-tetrazol-5-yl) biphen-4-yl) methylpyrido [3,4-d] pyrimidin-
4 ( 3H) -one 2-n-butylpyrido [3,4-d] pyrimidine-4
0.2 g (1.0 mmol) of (1H) -one was alkylated as in Example 4 above to yield 0.16 g (0.22 mmol) of a yellow oil after chromatography. ¹
_{H-NMR (CDCl 3):} 0.91 (t, 3H),
1.32 (m, 2H), 1.71 (m, 2H), 2.6
9 (t, 2H), 5.30 (bs, 2H), 6.89-
6.99 (m, 8H), 7.12 (d, 2H), 7.2
2-7.35 (m, 10H), 7.47 (m, 2H),
7.92 (dd, 1H), 8.07 (d, 1H), 8.
69 (d, 1H), 9.12 (s, 2H).

Deprotected 2,3-dialkyl-pyridopyrimy
Production of gin-4 (3H) -one

Example 7 2-n-butyl-3- (2 '-(tetrazo
Ol-5-yl) bifen-4-aLe) methylpyrido
[2,3-d] pyrimidin-4 (3H) -one Mixture of 0.9 ml acetic acid, 0.3 ml water and 0.3 ml THF
-Butyl-3- (2 '-(N-triphenylmethyl-te
Trazol-5-yl) biphen-4-yl) methylpi
Dissolution of Lido [2,3-d] pyrimidin-4 (3H) -one
The liquid was heated to reflux for 45 minutes. The reaction mixture in vacuum
Concentrate the residue to 70: 30: 1 EtAc: Hexane:
Flash chromatography on silica gel eluting with acetic acid
30.4 mg (0.068)
(Mmol).¹ H-NMR (CDCl₃ ): 0.
83 (t, 3H, J = 7.3 Hz), 1.32 (m, 2)
H), 1.68 (m, 2H), 2.71 (t, 2H, J
= 7.8 Hz), 5.32 (bs, 2H), 7.01
(S, 8H), 7.32-7.55 (m, 8H), 7.
84 (d, 1H, J = 7.7 Hz), 8.54 (dd,
1H, J = 7.8, 1.9 Hz), 8.75 (dd, 1
H, J = 1.9, 4.4 Hz), 9.4 (bs, 1)
H). FABMS: m / z 438 (M⁺ +1).

[0084]

Example 8 2-n-butyl-3- (2 '-(tetrazo
Ol-5-yl) bifen-4-aLe) methylpyrido
[3,2-d] pyrimidin-4 (3H) -one 2-n-butyl-3- (2 '-(N-triphenylteto
Razol-5-yl) biphen-4-yl) methylpyri
Do [3,2-d] pyrimidin-4 (3H) -one is described above.
When hydrolyzed as in Example 7, 50: 10: 30: 1
Silica eluting with EtAc: MeOH: hexane: acetic acid
After purification by flash chromatography on gel
The title compound was obtained.¹ H-NMR (CD₃ OD): 0.
91 (t, 3H, J = 7.3 Hz), 1.40 (m, 2
H), 1.74 (m, 2H), 2.82 (t, 2H, J
= 7.8 Hz), 5.47 (bs, 2H), 7.0-
7.3 (m, 9H), 7.42-7.65 (m, 8)
H), 7.84 (d, 1H, J = 2.1 Hz), 8.1
5 (d, 1H, J = 8.1 Hz), 8.17 (m, 1
H). FABMS: m / z 438 (M⁺ +1).

[0085]

Example 9 2-n-butyl-3- (2 '-(tetrazo
Ol-5-yl) bifen-4-aLe) methylpyrido
[3,4-d] pyrimidin-4 (3H) -one 2-n-butyl-3- (2 '-(N-triphenylteto
Razol-5-yl) biphen-4-yl) methylpyri
Do [3,4-d] pyrimidin-4 (3H) -one
70: 29: 1 E when hydrolyzed as described in Example 6
silica gel eluting with tAc: hexane: acetic acid.
After purifying by rush chromatography,
Obtained.¹ H-NMR (CD₃ OD): 0.82 (t, 3
H, J = 7.38 Hz), 1.33 (m, 2H), 1.
69 (m, 2H), 2.71 (t, 2H, J = 7.9H
z), 5.37 (bs, 2H), 7.04 (m, 8)
H), 7.42-7.61 (m, 8H), 7.99.
(D, 1H, J = 5.4 Hz), 8.51 (d, 1H,
J = 4.5 Hz), 8.92 (s, 1H). FABM
S: m / z 438 (M⁺ +1).

[0086]

Example 10 Representative Pharmaceutical Composition Containing a Compound of the Invention A. Dose- filled capsule ingredients containing 50 mg of active ingredient per capsule / capsule (mg) 2-n-butyl-3-[(2′-tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2 , 3-d] pyrimidin-4 (3H) -one 50 lactose 149 magnesium stearate 1 capsule (size No. 1) 200 2-n-butyl-3-[(2′-tetrazol-5-yl) biphen-4 -Yl) methyl] pyrido [2,3-
The d] pyrimidin-4 (3H) -one can be ground to a No. 60 powder and then the lactose and magnesium stearate can be passed through this powder with a No. 60 blotting cloth. Next, add about 1
Mix for 0 minutes and fill into No. 1 dry gelatin capsule.

B. Tablets A typical tablet is 2-n-butyl-3-[(2'-tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H) -one ( 25
mg), pre-gelling starch USP (82 mg), microcrystalline cellulose (82 mg) and magnesium stearate (1 m
g) is included.

C. Combination Tablets Typical combination tablets contain a diuretic such as hydrochlorothiazide and include 2-n-butyl-3-[(2′-tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3 -D] pyrimidin-4 (3H) -one (5
0 mg), pre-gelling starch USP (82 mg), microcrystalline cellulose (82 mg) and magnesium stearate (1
mg).

D. A typical suppository formulation for rectal administration is 2-n-butyl-3-.
[(2'-Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3
H) -one (0.08-1.0 mg), disodium calcium edetate (0.25-0.5 mg) and polyethylene glycol (775-1600 mg) can be included. Other suppository formulations include, for example, disodium calcium edetate butylated hydroxytoluene (0.0
4-0.08mg) with polyethylene glycol saposia
(Suppocire) L. Wecobee FS Wecobee M. It can be prepared by substituting hydrogenated vegetable oil (675 to 1400 mg) such as Witepsols. Furthermore, these suppository formulations may contain other antihypertensive agents and / or diuretics and / or other active ingredients such as angiotensin converting enzyme inhibitors and / or calcium channel blockers, eg pharmaceutically effective agents as described under C above. It can also be included in an amount.

E. Injectable formulation A typical injectable formulation is 2-N-butyl-3-[(2'-
Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H) -one, dibasic sodium phosphate anhydrous (11.4 mg),
Benzyl alcohol (0.01 ml) and water for injection (1.
0 ml). Such injectable formulations also contain a pharmaceutically effective amount of other antihypertensive and / or diuretics and / or other active ingredients such as angiotensin converting enzyme inhibitors and / or calcium channel blockers. You can also

Continued Front Page (72) Inventor Stephen E. De Laszlo United States, 07716 New Jersey, Atlantic Highlands, Monmouth Avenue 178 (72) Inventor William J. J. Greenley United States, 07666 New Jersey, Teaneck, Herrick Avenue 115 (72) Inventor Arthur A. Patchett United States, 07090 New Jersey, Westfield, Mini Think Way 1090 (72) Inventor Thomas F. Walsh United States, 07090 New Jersey, Westfield, Marion Avenue 127 (56) References JP-A-3-44377 (JP, A)

Claims (10)

[Claims] 1. Formula (I): [In the Formula, M is a C atom. L is C or N and when attached to K or J forms a ring as defined below. J is -C (= Y)-(Y is O or NR ²¹ ) and K
And L are joined together to form a 6-membered aromatic ring containing one N atom and five C atoms which is not K, with carbon atoms substituted by R ⁷ , R ^8a and R ^8b be able to. K is-
C (= Y)-(Y is O or NR ²¹ ), J and L are bonded together and are a 6-membered aromatic containing one N atom and five C atoms which are not J's. A ring can be formed and the carbon atom can be substituted with R ⁷ , R ^8a and R ^8b . However, only one of J and K is -C (= Y)-. R ¹ is ^{_{(a) -CO 2 R 4,}} (b) -SO 3 R 5, (c) -NHSO 2 CF 3, (d) -PO (OR 5) 2, (e) -SO 2 -NH- ^{R 9, (f) -CONHOR 5} , (g) -C (OH) (R 9) -P (= O) (OR 5)
^{(OR 5), (h)} -P (= O) (R 9) (OR 5) (k) -SO 2 NH-CO-R 22, (l) -CH 2 SO 2 NH-CO-R 22, _{(m) -CONH-SO 2 R} 22, (n) -CH 2 CONH-SO 2 R 22, (o) -NHSO 2 NHCO-R 22, (p) -NHCONHSO 2 -R 22, ## STR2 ## (T) -CONHNHSO ₂ CF ₃ , (u) -SO ₂ NH-CN, ^{(X) -PO (OR 5)} (OR 4), (y) -SO 2 NHCONR 4 R 22, R 2a and R ^2b are each independently (a) H, (b) halogen (Cl, Br, I , F), (c) NO ₂ , (d) NH ₂ , (e) C ₁ -C ₄ -alkylamino, (f) di (C ₁ -C ₄ -alkyl) amino, (g) SO ₂ NHR ⁹ _{, (h) CF 3, (} i) C 1 ~C 6 - _{alkyl, (j) C 1 ~C 6} - _{alkoxy, (k) C 1 ~C 6} - alkyl -S-, (l) C ₂ ~C ₆ - _{alkenyl, (m) C 2 ~C 6} - alkynyl, aryl as defined below (n), (o) aryl (C ₁ -C ₄ - _{alkyl), (p) C 3 ~C} 7 - cycloalkyl Is. R ^3a is (a) H, (b) halo (Cl, Br, I, F), (c) C ₁ -C ₆ -alkyl, (d) C ₁ -C ₆ -alkoxy, (e) C _1- . C ₆ - alkoxyalkyl. R ^3b is (a) H, (b) halo (Cl, Br, I, F), (c) NO ₂ , (d) C ₁ -C ₆ -alkyl, (e) C ₁ -C ₆ -acyloxy, (f) C ₃ ~C ₇ - _{cycloalkyl, (g) C 1 ~C 6} - ^{_{alkoxy, (h) -NHSO 2 R 4}} , (i) hydroxy (C ₁ ~C ₄ - alkyl), (j) aryl (C ₁ -C ₄ -alkyl), (k) C ₁ -C ₄ -alkylthio, (l) C ₁ -C ₄ -alkylsulfinyl, (m) C ₁ -C ₄ -alkylsulfonyl, (n) NH _{2. , (o) C 1 ~C 4} - alkylamino, (p) di (C _{1 ~C 4} - alkyl) amino, (q) fluoro -C ₁ -C ₄ - alkyl -, (r) -SO ₂ -NHR ^9, (s) aryl as defined below, (t) _{furyl, (u) CF 3, (} v) C 2 ~C 6 - alkenyl, (w ) C ₂ ~C ₆ - alkynyl, {aryl halogen (Cl, Br, I, F ), N (R
⁴ ) ₂ , CO ₂ R ⁴ , C ₁ -C ₄ -alkyl, C ₁ -C
₄ - _{alkoxy, NO 2, CF 3, C} 1 ~C 4 - is alkylthio or one or two phenyl or naphthyl which is optionally substituted with substituents selected from the group consisting of OH}. R ⁴ is H, aryl as defined above or straight or branched C ₁ -C ₆ -alkyl optionally substituted with aryl as defined above. R ^4a is aryl as defined above or straight or branched C ₁ -C ₆ -alkyl optionally substituted with aryl as defined above. R ⁵ is H, -CH (R ⁴⁾ is -O-C (= O) -R 4a. E is a single _{^{bond, -NR 13 (CH 2) s}} -, - S (O) x
(CH _{2) s} - (x is 0 to 2, s is 0~5), - CH (OH) -, - O -, - is CO-. R ⁶ is (a) halo (Cl, Br, I, F), —O—C ₁
-C ₄ - alkyl, C ₁ ~C ₄ - alkyl, -NO _{2,
^{-CF 3, -SO 2 NR 9 R}} 10, -S-C 1 ~C 4 - _{alkyl, -OH, -NH 2, C 3} ~C 7 - cycloalkyl, C ₃ ~C ₁₀ - from the group consisting of alkenyl Phenyl or naphthyl optionally substituted with one or two selected substituents. (B) Linear or branched C ₁ -C ₆ -alkyl, C ₂ -C
₅ - alkenyl or C ₂ -C ₅ - alkynyl {aryl defined on each, C ₃ -C ₇ - cycloalkyl, halo (Cl, Br, I, F ), CF 3, CF 2 CF 3, -N
_{H 2, -NH (C 1 ~C} 4 - alkyl), - OR ^4, -
N (C ₁ ~C ₄ - _{alkyl) 2, -NH-SO 2 R} 4,
Optionally substituted with a substituent selected from the group consisting of —COOR ⁴ , —SO ₂ NHR ⁹ } or (d) C ₃ -C ₇ -cycloalkyl, (e) perfluoro-C ₁ -C ₄ -alkyl, (f) H. R ⁷ is (a) H, (b) straight or branched chain C ₁ -C ₆ -alkyl, C ₂ -C
₆ - alkenyl or C ₂ -C ₆ - alkynyl, (c) halo (Cl, Br, I, F ) or (d) CF _3. R ^8a and R ^8b are independently (a) H, (b) -OH, - guanidino, C ₁ ~C ₄ - _{^{alkoxy, -N (R 4) 2,}} COOR 4, -CON (R 4)
_2, -O-COR ^4, - aryl, -S (O) _x -
R ^22, - tetrazol-5-yl, -CONHSO ₂ R
_{^{22, -SO 2 NHCOR 22, -PO}} (OR 4) 2, -P
^{O (OR 4) R 9,} -SO 2 NH-CN, -NR 10 CO
_{^{OR 22, - (CH 2)}} 1-4 C is optionally substituted with substituents selected from the group consisting of R ⁴ ₁ ~C ₈ - alkyl, (c) -CO- aryl, (d) -C ₃ -C ₇ - cycloalkyl, (e) halo (Cl, Br, I, F ), (f) -OH, (g) -OR 22, (h) -C 1 ~C 4 - perfluoroalkyl, (i ^{_{) -S (O) x -R 22}} , (j) -COOR 4, (k) -SO 3 H, (l) -NR 4 R 22, (m) -NR 4 COR 22, (n) -NR 4 _{^{COOR 22, (o) -SO 2}} NR 4 R 9, (p) -NO 2, (q) -N (R 4) SO 2 R 22, (r) -NR 4 CONR 4 R 22, (s) - ^{OC (= O) NR 22 R} 9, as defined above (t) - _{aryl, (u) -NHSO 2 CF 3} , (w) -SO 2 NHCOR 22, (x) -CONHSO 2 R 22, ( _{^{y) -PO (OR 4) 2}} , (z) -PO (OR 4) R 4, (aa) - tetrazol-5-yl, (bb) -CONH (tetrazol-5-yl), (cc) -COR _{^{4, (dd) -SO 2 NHCN}} , (ee) -NR 4 SO 2 NR 4 R 22, (ff) -NR 4 SO 2 OR 22, (gg) -CONR 4 R 22, embedded image Is. R ⁹ is H, C ₁ -C ₅ -alkyl, aryl or arylmethyl. R ¹⁰ is H, C ₁ -C ₄ -alkyl. R ¹¹ is H, C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkenyl, C ₁ -C ₄ -alkoxyalkyl or Is. R ¹² is -CN, a -NO ₂ or -CO ₂ R ^4. R ¹³ is H, (C ₁ -C ₄ -alkyl) CO—, C ₁ -C
₆ - alkyl, allyl, C ₃ -C ₆ - cycloalkyl,
Aryl or arylmethyl. R ¹⁴ is H, C ₁ -C ₈ -alkyl, C ₁ -C ₈ -perfluoroalkyl, C ₃ -C ₆ -cycloalkyl, aryl or arylmethyl. R ¹⁵ is H, C ₁ -C ₆ -alkyl. R ¹⁶ is H, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, aryl or arylmethyl. R ¹⁷ is ^{-NR 9 R 10, -OR 10,} -NHCONH 2, -
NHCSNH ₂ , embedded image Is. R ¹⁸ and R ¹⁹ are independently C ₁ -C ₄ -alkyl or linked together are — (CH ₂ ) _q — (q is 2 or 3). R ²⁰ is _{H, -NO 2, -NH 2,} -OH or -OCH ₃
Is. R ²¹ is aryl as defined above in (a), aryl as defined above in (c), —OH, —NH ₂ , —N.
H (C ₁ ~C ₄ - _{alkyl), - N (C 1 ~C} 4 - alkyl) _2, -CO ₂ R ^4a, halo (Cl, Br, F,
I), - C is optionally substituted with substituents selected from the group consisting of CF _{3 1} ~C ₄ - alkyl. R ²² is (a) aryl as defined above, (c) C ₃ -C ₇ -cycloalkyl, (d) aryl as defined above, —OH, —SH, C _1- .
C ₄ - alkyl, -O (C ₁ ~C ₄ - alkyl), - S
(C ₁ ~C ₄ - alkyl), - CF _3, halo (Cl, B
r, F, I), - NO 2, -CO 2 H, -CO 2 - (C
₁ -C ₄ - _{alkyl), - NH 2, -NH (} C 1 ~C 4
- _{alkyl), - N (C 1 ~C} 4 - alkyl) _2, -P
C ₁ -C ₆ optionally substituted with a substituent selected from the group consisting of O ₃ H ₂ , -PO (OH) (O-C ₁ -C ₄ -alkyl), -PO (OR ⁴ ) R ^9. - alkyl, (e) perfluoro -C ₁ -C ₄ - alkyl. X is (a) carbon-carbon single bond (b) -CO-, (c) -O-, (d) -S-, (e) -N (R < ¹³ >)-, (f) -CON (R < ¹⁵ >). ) -, (g) - ( R 15) NCO-, (h) -OCH 2 -, (i) -CH 2 O-, (j) -SCH 2 -, (k) -CH 2 S-, (l ^{) -NHC (R 9) (R} 10), (m) -NR 9 SO 2 -, (n) -SO 2 NR 9 -, (o) -C (R 9) (R 10) NH-, (p ) -CH = CH-, (q) -CF = CF-, (r) -CH = CF-, (s) -CF = CH-, (t) -CH 2 CH 2 -, (u) -CF 2 CF ₂ −, embedded image ^{(W) -C (OR 14)} H-, (x) -C (OCOR 16) H-, (y) -C (= NR 17) -, or embedded image Is. r is 1 or 2 (provided that 2-n-butyl-
3-[(2 '-(tetrazol-5-yl) biphen-
4-yl) methyl] pyrido [2,3-d] pyrimidine-
4 (3H) -one and 2-n-butyl-3-[(2'-
A compound represented by (tetrazol-5-yl) biphen-4-yl) methyl] pyrido [3,2-d] pyrimidin-4 (3H) -one)] and a pharmaceutically usable salt thereof. 2. M is a C atom, J is —C (O) —, and K and L are joined together to contain one N atom and no C but 5 C atoms. A membered aromatic ring can be substituted on the carbon atom with R ⁷ , R ^8a and R ^8b ,
R ¹ is (a) -COOH, _{(C) -NH-SO 2 CF} 3, (f) -SO 2 NH-CO-R 22, (g) -CH 2 SO 2 NH-CO-R 22, (h) -CONH-SO 2 R 22, _{(i) -CH 2 CONH-SO} 2 R 22, (j) -NHSO 2 NHCO-R 22, a ^{_{(k) -NHCONHSO 2 -R 22,}} R 2a is H, R ^2b is H, F, _{Cl, CF 3, C 1 ~C} 6 - alkyl,
C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl or aryl, R ^3a is H, R ^3b is _{H, F, Cl, CF 3} , C 1 ~C 4 - alkyl,
C ₂ -C ₄ - alkenyl, C ₂ ~C ₄ - alkynyl, C
₅ -C ₆ - cycloalkyl, -COOCH _3, -COO
_{C 2 H 5, -SO 2 -CH} 3, NH 2, -N (C 1 ~C
₄ -alkyl) ₂ or -NH-SO ₂ CH ₃ , E is a single bond, -O- or -S-, and R ⁶ is (a) C ₃ -C ₅ -cycloalkyl, Cl, CF.
_{3, CCl 3, -O-CH} 3, -OC 2 H 5, -S-C
_{H 3, -S-C 2 H} 5, phenyl or C, optionally substituted with substituents selected from the group consisting of F ₁ -C ₅ - _{alkyl, (b) C 2 ~C 5} - alkenyl or C ₂ -C ₅ - alkynyl or (c) C ₃ ~C ₅ - cycloalkyl, R ⁷ is H, R ^8a and R ^8b are independently (a) H, (b) COOR 4a, OCOR 4a, OH, aryl or-
(CH ₂₎ C ₁ optionally substituted with _1-4 R ⁴ _{~C 8} - ^{alkyl, (c) OR 22, (} d) -OH, (e) -NO 2, (f) -NR 4 -C ^{(= O) -R 22, (} g) -CONR 4 R 22, (h) -NR 4 -C (= O) -O-R 22, (i) -NR 4 R 22, (j) halo (Cl , F, Br), (k ) -CF 3, (l) -CO 2 R 4a, -CO- aryl as defined above (m), (n) -S (O) x -R 22, (o) _{^{-SO 2 -NR 4 R 9 (p}} ) -N (R 4) SO 2 R 22, aryl as defined above (q), (r) -NR 4 CONR 4 R 22, (s) -N (R 4 ) SO ₂ N (R ⁴⁾ is R ^22, X is a single bond, the compound of claim 1 wherein r is 1. 3. (1) 2-n-butyl-1-[(2'-
Carboxybiphen-4-yl) methyl] pyrido-
[2,3-d] pyrimidin-4 (1H) -one, (2) 2-n-butyl-1-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2 , 3-d] Pyrimidin-4- (1H) -one, (3) 2-n-butyl-1-[(2 ′-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [3. 2-d] pyrimidin-4- (1H) -one, (4) 2-n-butyl-1-[(2 ′-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [3,4] -D] pyrimidin-4- (1H) -one, (5) 2-n-butyl-1-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [4,3- d] pyrimidin-4- (1H) -one, (6) 2-n-butyl-6-methyl-1-[(2'-
(Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4- (1H)-
ON, (7) 6-amino-2-n-butyl-1-[(2'-
(Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4- (1H)-
On, (8) 2-n-butyl-1-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl-8-methyl] pyrido [4,3-d] pyrimidine-4- ( 1H)-
On and (9) 2-n-butyl-1-5-methyl-[(2'-
(Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [3,4-d] pyrimidin-4- (1H)-
ON, (10) 2-n-butyl-5,7-dimethyl-1-
(2 '-(Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (1
H) -one, (11) 6-amino-2-n-butyl-5-methyl-1
-[(2 '-(tetrazol-5-yl) biphen-4
-Yl) methyl] pyrido [2,3-d] pyrimidine-4
(1H) -one, (12) 2-n-butyl-5-methyl-7-methylamino-1-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2. 3-d] pyrimidin-4 (1H) -one, (13) 1-[(2 ′-(N-benzoylsulfonamido) biphen-4-yl) methyl] -2-n-butyl-
5,7-Dimethylpyrido [2,3-d] pyrimidine-4
-(1H) -one and (14) 2-n-butyl-5,7-dimethyl-1-
The selected from the group consisting of [(2 '-(N-trifluoromethyl] sulfonylcarboxamido) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (1H) -one. Compound of. 4. M is a C atom, K is —C (O) —, and J and L are linked together to contain one N atom and five C atoms which are not J's. to form a 6-membered aromatic ring, the carbon atoms can be substituted with R ^7, R ^8a and R ^8b, R ¹
Is (a) -COOH, _{(C) -NH-SO 2 CF} 3, (f) -SO 2 NH-CO-R 22, (g) -CH 2 SO 2 NH-CO-R 22, (h) -CONH-SO 2 R 22, _{(i) -CH 2 CONH-SO} 2 R 22, (j) -NHSO 2 NHCO-R 22, a ^{_{(k) -NHCONHSO 2 -R 22,}} R 2a is H, R ^2b is H, F, _{Cl, CF 3, C 1 ~C} 6 - alkyl,
C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl or aryl, R ^3a is H, R ^3b is _{H, F, Cl, CF 3} , C 1 ~C 4 - alkyl,
C ₂ -C ₄ - alkenyl, C ₂ ~C ₄ - alkynyl, C
₅ -C ₆ - cycloalkyl, -COOCH _3, -COO
_{C 2 H 5, -SO 2 -CH} 3, NH 2, -N (C 1 ~C
₄ -alkyl) ₂ or -NH-SO ₂ CH ₃ , E is a single bond, -O- or -S-, and R ⁶ is (a) C ₃ -C ₅ -cycloalkyl, Cl, CF.
_{3, CCl 3, -O-CH} 3, -OC 2 H 5, -S-C
_{H 3, -S-C 2 H} 5, optionally substituted C ₁ -C ₅ alkyl substituents selected from the group consisting of phenyl or _{F, (b) C 2 ~C} 5 - alkenyl or C ₂ ~ C ₅ - alkynyl or (c) C ₃ ~C ₅ - cycloalkyl, R ⁷ is H, R ^8a and R ^8b are independently (a) H, (b) COOR 4a, OCOR 4a, OH , Aryl or-
(CH _{2) 1-4} R ⁴ optionally substituted with a C ₁ -C ₈ - ^{alkyl, (c) -OR 22, (} d) -OH, (e) -NO 2, (f) -NR 4 - ^{C (= O) -R 22,} (g) -CONR 4 R 22, (h) -NR 4 -C (= O) -O-R 22, (i) -NR 4 R 22, (j) halo ( Cl, F, Br), ( k) -CF 3, (l) -CO 2 R 4a, (m) -CO- as defined above aryl, (n) -S (O) x -R 22, (o _{^{) -SO 2 -NR 4 R 9,}} (p) -N (R 4) SO 2 R 22, aryl as defined above (q), (r) -NR 4 CONR 4 R 22, (s) -N ( The compound according to claim 1, wherein R ⁴ ) SO ₂ N (R ⁴ ) R ²² , X is a single bond, and r is 1. 5. R ¹ is (a) -COOH; _{(C) -NH-SO 2 -CF} 3, (e) -SO 2 NH-CO-R 22, (f) a -CONH-SO ₂ R ^22, E is a single bond, r is 1 , R ^2a , R ^2b , R ^3a and R ^3b are each H, -C ₁ -C ₆ -alkyl, -C ₂ -C ₆ -alkenyl, -C ₂ -C ₆ -alkynyl, -Cl, -F,-. NO _2, a -CF _3, R ⁶ is -C ₁ -C ₄ - alkyl, - cyclopropyl, -
_{CH 2 CH 2 CH 2 CF 3} , -CH 2 CH 2 CF 3, -
C ₂ -C ₅ - alkenyl, - cyclopropylmethyl, H are independently R ^8a and R ^8b are each, -C ₁ -C ₄ - _{^{alkyl, -NO 2, -NR 4 R 22}} , -OCH 3, -NR ⁴ C
OOR ²² , -Cl, -CH ₂ COOR ^4a , -S (O) _x.
-R ²² - ^{alkyl, NR 4 CONR 4 R 22,} CH 2 OC
O (C ₁ ~C ₄ - ^{alkyl), NR 4 COR 22, CO} 2
The compound according to claim 4, which is R ^4a , —F, —CH ₂ Ph, or —CONR ⁴ R ²² . 6. (1) 2-n-butyl-3-[(2′-
Carboxybiphen-4-yl) methyl] pyrido [2,2
3-d] pyrimidin-4 (3H) -one, (3) 2-n-butyl-3-[(2′-carboxybiphen-4-yl) methyl] pyrido [3,2-d] pyrimidin-4 (3H) -one, (4) 2-n-butyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [4,3-d] pyrimidin-4 (3H ) -One, (5) 2-n-butyl-7-isopropyl-3-
[(2 '-(Tetrazol-5-yl) biphen-4-
Il) methyl] pyrido [4,3-d] pyrimidine-4
(3H) -one, (6) 6-amino-2-n-butyl-3-[(2'-
(Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H) -one, (7) 6-acetamido-2-n-butyl-3-[(2 '
-(Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H)-
ON, (8) 2-n-butyl-5-methyl-3-[(2'-
(Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [3,4-d] pyrimidin-4 (3H) -one, (9) 2-n-butyl-3-[(2 '-(tetrazole -5-yl) biphen-4-yl) methyl-6-thiomethylpyrido [2,3-d] pyrimidin-4 (3H) -one, (10) 2-n-butyl-7-carboxy-3-
[(2 '-(Tetrazol-5-yl) biphen-4-
Il) methyl] pyrido [2,3-d] pyrimidine-4
(3H) -one, (11) 2-n-butyl-7- (N-isopropylcarbamoyl) amino-3-[(2 '-(tetrazole-5
-Yl) biphen-4-yl) methyl] pyrido [3,2
-D] pyrimidin-4 (3H) -one, (12) 2-n-butyl-6- (N-isobutyloxycarbonyl) amino-3-[(2 '-(tetrazole-
5-yl) biphen-4-yl) methyl] pyrido [2,2
3-d] pyrimidin-4 (3H) -one, (13) 2-n-butyl-6- [N- (morpholine-4
-Yl) carbamoyl) -N-methyl] amino-3-
[(2'-Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3
H) -one, (14) 2-n-butyl-6- (N-isopropyloxycarbonyl-N-methyl) -amino-3-[(2'-
Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H) -one, (15) 6- (N-benzyloxycarbonyl-N-methyl) amino-2 -N-butyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H) -one, (16) 3- [ (2 '-(N-Benzoylsulfonamido) biphen-4-yl)] methyl-2-n-butyl-
6- (N-isopropyloxycarbonyl-N-benzyl) aminopyrido [2,3-d] pyrimidine-4 (3
H) -one, (17) 2-n-butyl-6- (N-isopropyloxycarbonyl-N-methyl) amino-3-[(2′-
(N-trifluoromethylsulfonylcarboxamide)
Biphen-4-yl) methyl] pyrido [2,3-d]-
Pyrimidin-4 (3H) -one, (19) 6- [N-benzyl-Nn-butyloxycarbonyl] amino-2-propyl-3-[(2 '-(tetrazol-5-yl) biphen-4 -Yl) methyl]
Pyrido [2,3-d] pyrimidin-4 (3H) -one, (20) 2-n-butyl-6- (N-methyl-N-isobutyloxycarbonyl) amino-3- [2 '-(tetrazole- 5-yl) biphen-4-yl) methyl] pyrido [3,2-d] pyrimidin-4 (3H) -one, (21) 6- (N-benzyl-N-butanoyl) amino-2-n-propyl. -3- [2 '-(tetrazole-5
-Yl) biphen-4-yl) methyl] pyrido [3,2
-D] pyrimidin-4 (3H) -one, (22) 6- (N-benzoyl-Nn-pentyl) amino-2-n-propyl-3- [2 '-(tetrazol-5-yl) biphene -4-yl) methyl] pyrido [3,2-d] pyrimidin-4 (3H) -one, (23) 6- (N- (p-chloro) benzoyl-Nn
-Pentyl) amino-2-n-propyl-3- [2'-
(Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [3,2-d] pyrimidin-4 (3H) -one, (24) 6- (N- (p-chloro) benzoyl-N-isobutyl ) Amino-2-n-propyl-3- [2'-
(Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [3,2-d] pyrimidin-4 (3H) -one, (25) 6- (Nn-propyl-N-isobutyloxycarbonyl) Amino-2-n-propyl-3- [2 '
-(Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [3,2-d] pyrimidin-4 (3H)-
ON, (26) 6- (N-benzoyl-Nn-pentyl) amino-3- [2 '-(N-benzoyl-sulfonamido) biphen-4-yl) methyl] -2-n-propylpyrido [3 , 2-d] Pyrimidin-4 (3H) -one, (27) 2-n-butyl-6- (N-methyl-N-isobutyloxycarbonyl) amino-3- [2 ′-(tetrazol-5-yl) ) Biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H) -one, (28) 6- (N-benzyl-N-butanoyl) amino-2-n-bropyr-3- [2 '-(tetrazole-5
-Yl) biphen-4-yl) methyl] pyrido [2,3
-D] pyrimidin-4 (3H) -one, (29) 6- (N- (p-chloro) benzoyl-Nn.
-Pentyl) amino-2-n-propyl-3- [2'-
(Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H) -one, (30) 6- (Nn-propyl-N-isobutyloxycarbonyl) Amino-2-n-propyl-3- [2 '
-(Tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H)-
On and (31) 6- (N-benzoyl-Nn-pentyl) amino-3- [2 '-(N-benzoylsulfonamide)
A compound according to claim 5 selected from the group consisting of biphen-4-yl) methyl] -2-n-propylpyrido [2,3-d] pyrimidin-4 (3H) -one. 7. A 6-membered member wherein M is a C atom, K is C = NR ²² and J and L are joined together to contain one N atom and five C atoms which are not J's. Forming an aromatic ring, the carbon atom of which can be substituted with R ⁷ , R ^8a and R ^8b ,
R ¹ is (a) -COOH, _{(C) -NH-SO 2 CF} 3, (f) -SO 2 NH-CO-R 22, (g) -CH 2 SO 2 NH-CO-R 22, (h) -CONH-SO 2 R 22, _{(i) -CH 2 CONH-SO} 2 R 22, (j) -NHSO 2 NHCO-R 22, a ^{_{(k) -NHCONHSO 2 -R 22,}} R 2a is H, R ^2b is H, F, _{Cl, CF 3, C 1 ~C} 6 - alkyl,
C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl or aryl, R ^3a is H, R ^3b is _{H, F, Cl, CF 3} , C 1 ~C 4 - alkyl,
C ₂ -C ₄ - alkenyl, C ₂ ~C ₄ - alkynyl, C
₅ -C ₆ - cycloalkyl, -COOCH _3, -COO
_{C 2 H 5, -SO 2 -CH} 3, NH 2, -N (C 1 ~C
₄ -alkyl) ₂ or -NH-SO ₂ CH ₃ , E is a single bond, -O- or -S-, and R ⁶ is (a) C ₃ -C ₅ -cycloalkyl, Cl, CF.
_{3, CCl 3, -O-CH} 3, -OC 2 H 5, -S-C
_{H 3, -S-C 2 H} 5, optionally substituted C ₁ -C ₅ alkyl substituents selected from the group consisting of phenyl or _{F, (b) C 2 ~C} 5 - alkenyl or C ₂ ~ C ₅ - alkynyl or (c) C ₃ ~C ₅ - cycloalkyl, R ⁷ is H, R ^8a and R ^8b are independently (a) H, (b) COOR 4a, OCOR 4a, OH , Aryl or-
(CH _{2) 1-4} R ⁴ optionally substituted with a C ₁ -C ₈ - ^{alkyl, (c) -OR 22, (} d) -OH, (e) -NO 2, (f) -NR 4 - ^{C (= O) -R 22,} (g) -CON 4 R 22, (h) -NR 4 -C (= O) -O-R 22, (i) -NR 4 R 22, (j) halo ( Cl, F, Br), ( k) -CF 3, (l) -CO 2 R 4a, (m) -CO- as defined above aryl, (n) -S (O) x -R 22, (O _{^{) -SO 2 -NR 4 R 9,}} (p) -N (R 4) SO 2 R 22, aryl as defined above (q), (r) -NR 4 CONR 4 R 22, (s) -N ( The compound according to claim 1, wherein R ^{4 is} SO ₂ N (R ⁴ ) R ²² , X is a single bond, and r is 1. 8. R ¹ is (a) -COOH, (b) embedded image _{(C) -NH-SO 2 -CF} 3, (e) -SO 2 NH-CO-R 22, (f) a -CONH-SO ₂ R ^22, E is a single bond, r is 1 , R ^2a , R ^2b , R ^3a and R ^3b are each H, -C ₁ -C ₆ -alkyl, -C ₂ -C ₆ -alkenyl, -C ₂ -C ₆ -alkynyl, -Cl, -F,-. NO _2, a -CF _3, R ⁶ is -C ₁ -C ₄ - alkyl, - cyclopropyl, -
_{CH 2 CH 2 CH 2 CF 3} , -CH 2 CH 2 CF 3, -
C ₂ -C ₅ - alkenyl, - cyclopropylmethyl, H are independently R ^8a and R ^8b are each, -C ₁ -C ₄ - _{^{alkyl, -NO 2, -NR 4 R 22}} , -OCH 3, -NR ⁴ C
OOR ²² , -Cl, -CH ₂ COOR ^4a , -S (O) _x.
-R ²² - ^{alkyl, NR 4 CONR 4 R 22,} CH 2 OC
O (C ₁ ~C ₄ - ^{alkyl), NR 4 COR 22, CO} 2
_{^{R 4a, -F, -CH 2 Ph}} , the compound of claim 7 wherein the -CONR ⁴ R ^22. 9. (1) N-methyl 2-n-butyl-3-
[(2 '-(Tetrazol-5-yl) biphen-4-
Il) methyl] pyrido [2,3-d] pyrimidine-4
(3H) -imine, (2) N-benzyl 2-n-butyl-3-[(2'-
(Tetrazol-5-yl) biphen-4-yl) methyl] -5-methylpyrido [3,4-d] pyrimidin-4
(3H) -imine, (3) N-phenyl-5-amino-2-n-butyl-3
-[(2 '-(tetrazol-5-yl) biphen-4
-Yl) methyl] pyrido [2,3-d] pyrimidine-4
(3H) -imine, (4) N-methyl 2-n-butyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl]
-6-Isopropylpyrido [3,2-d] pyrimidine-
4 (3H) -imine, (5) N-butyl 2-n-butyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl]
-5- (N-isopropylcarbamoyl) aminopyrido [2,3-d] pyrimidine-4 (3H) -imine, (6) N-methyl 2-n-butyl-6- [N- (N-isopropylcarbamoyl)- N-methyl] amino-3-
[(2 '-(Tetrazol-5-yl) biphen-4-
Il) methyl] pyrido [2,3-d] pyrimidine-4
(3H) -imine, (7) N-propyl 2-n-butyl-6- [N- (morpholin-4-yl-carbamoyl) -N-methyl] amino-3-[(2 '-(tetrazole-5 -Yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H) -imine, (8) N-methyl 2-n-butyl-6- (N-isopropyloxycarbonyl-N -Methyl) amino-3-
[(2 '-(Tetrazol-5-yl) biphen-4-
Il) methyl] pyrido [2,3-d] pyrimidine-4
(3H) -imine, (9) N-benzyl 6- (N-benzyloxycarbonyl-N-methyl) amino-2-n-butyl-3-
[(2 '-(Tetrazol-5-yl) biphen-4-
Il) methyl] pyrido [2,3-d] pyrimidine-4
(3H) -imine, (10) N-methyl 3-[(2 '-(N-benzoylsulfonamido) biphen-4-yl) methyl] -2-n
-Butyl-6- (N-isopropyloxycarbonyl-
N-methyl) aminopyrido [2,3-d] pyrimidine-
4 (3H) -imine and (11) N-methyl 2-n-butyl-6- (N-isopropyloxycarbonyl-N-methyl) amino-3-
The selected from the group consisting of [(2 '-(N-trifluoromethylsulfonyl-carboxamido) bifen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (3H) -imine. Compound of. 10. A pharmaceutically acceptable carrier and claim 1.
A pharmaceutical composition useful in the treatment of hypertension comprising a pharmaceutically effective amount of the described compound.